Quinoline derivatives as PI3 kinase inhibitors

ABSTRACT

Invented is a method of inhibiting the activity/function of PI3 kinases using quinoline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinoline derivatives.

This application claims the benefit of U.S. Provisional Application No.60/938,761, filed May 18, 2007, which is herein incorporated byreference.

FIELD OF THE INVENTION

This invention relates to the use of quinoline derivatives for themodulation, notably the inhibition of the activity or function of thephosphoinositide 3′ OH kinase family (hereinafter PI3 kinases),suitably, PI3Kα, PI3Kδ, PI3Kβ, and/or PI3Kγ, particularly PI3Kα.Suitably, the present invention relates to the use of quinolinesderivatives in the treatment of one or more disease states selectedfrom: autoimmune disorders, inflammatory diseases, cardiovasculardiseases, neurodegenerative diseases, allergy, asthma, pancreatitis,multiorgan failure, kidney diseases, platelet aggregation, cancer, spermmotility, transplantation rejection, graft rejection and lung injuries,particularly cancer.

BACKGROUND OF THE INVENTION

Cellular membranes represent a large store of second messengers that canbe enlisted in a variety of signal transduction pathways. In regardsfunction and regulation of effector enzymes in phospholipids signalingpathways, these enzymes generate second messengers from the membranephospholipid pools (class I PI3 kinases (e.g. PI3Kalpha) aredual-specificity kinase enzymes, meaning they display both: lipid kinase(phosphorylation of phosphoinositides) as well as protein kinaseactivity, shown to be capable of phosphorylation of protein assubstrate, including auto-phosphorylation as intramolecular regulatorymechanism. These enzymes of phospholipids signaling are activated inresponse to a variety of extra-cellular signals such as growth factors,mitogens, integrins (cell-cell interactions) hormones, cytokines,viruses and neurotransmitters such as described in Scheme I hereinafterand also by intracellular regulation by other signaling molecules(cross-talk, where the original signal can activate some parallelpathways that in a second step transmit signals to PI3Ks byintra-cellular signaling events), such as small GTPases, kinases orphosphatases for example. Intracellular regulation can also occur as aresult of aberrant expression or lack of expression of cellularoncogenes or tumor suppressors. The inositol phospholipid(phosphoinositides) intracellular signaling pathways begin withactivation of signaling molecules (extra cellular ligands, stimuli,receptor dimerization, transactivation by heterologous receptor (e.g.receptor tyrosine kinase) and the recruitment and activation of PI3Kincluding the involvement of G-protein linked transmembrane receptorintegrated into the plasma membrane.

PI3K converts the membrane phospholipid PI(4,5)P₂ into PI(3,4,5)P₃ thatfunctions as a second messenger. PI and PI(4)P are also substrates ofPI3K and can be phosphorylated and converted into PI3P and PI(3,4)P₂,respectively. In addition, these phosphoinositides can be converted intoother phosphoinositides by 5′-specific and 3′-specific phophatases, thusPI3K enzymatic activity results either directly or indirectly in thegeneration of two 3′-phosphoinositide subtypes that function as 2^(nd)messengers in intra-cellular signal transduction pathways (TrendsBiochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et al.: Chem.Rev. 101(8) p. 2365-80 (2001) by Leslie et al (2001); Annu. Rev. Cell.Dev. Biol. 17p, 615-75 (2001) by Katso et al. and Cell. Mol. Life. Sci.59(5) p. 761-79 (2002) by Toker et al.). Multiple PI3K isoformscategorized by their catalytic subunits, their regulation bycorresponding regulatory subunits, expression patterns andsignaling-specific functions (p110α, β, δ and γ) perform this enzymaticreaction (Exp. Cell. Res. 25 (1) p. 239-54 (1999) by Vanhaesebroeck andKatso et al., 2001, above).

The closely related isoforms p110α and β are ubiquitously expressed,while δ and γ are more specifically expressed in the haematopoietic cellsystem, smooth muscle cells, myocytes and endothelial cells (TrendsBiochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et al.). Theirexpression might also be regulated in an inducible manner depending onthe cellular, tissue type and stimuli as well as disease context.Inducibility of protein expression includes synthesis of protein as wellas protein stabilization that is in part regulated by association withregulatory subunits.

To date, eight mammalian PI3Ks have been identified, divided into threemain classes (I, II, and III) on the basis of sequence homology,structure, binding partners, mode of activation, and substratepreference. In vitro, class I PI3Ks can phosphorylatephosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), andphosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) to producephosphatidylinositol-3-phosphate (PI3P),phosphatidylinositol-3,4-bisphosphate (PI(3,4)P₂, andphosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃, respectively.Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate.Class III PI3Ks can only phosphorylate PI (Vanhaesebrokeck et al., 1997,above; Vanhaesebroeck et al., 1999, above and Leslie et al, 2001, above)

As illustrated in Scheme A above, phosphoinositide 3-kinases (PI3Ks)phosphorylate the hydroxyl of the third carbon of the inositol ring. Thephosphorylation of phosphoinositides that generate PtdIns to3,4,5-trisphosphate (PtdIns(3,4,5)P₃), PtdIns(3,4)P₂ and PtdIns(3)Pproduce second messengers for a variety of signal transduction pathways,including those essential to cell proliferation, cell differentiation,cell growth, cell size, cell survival, apoptosis, adhesion, cellmotility, cell migration, chemotaxis, invasion, cytoskeletalrearrangement, cell shape changes, vesicle trafficking and metabolicpathway (Katso et al., 2001, above and Mol. Med. Today 6(9) p. 347-57(2000) by Stein). G-protein coupled receptors mediate phosphoinositide3′OH-kinase activation via small GTPases such as Gβγ and Ras, andconsequently PI3K signaling plays a central role in establishing andcoordinating cell polarity and dynamic organization of thecytoskeleton—which together provides the driving force of cells to move.Chemotaxis—the directed movement of cells toward a concentrationgradient of chemical attractants, also called chemokines is involved inmany important diseases such as inflammation/auto-immunity,neurodegeneration, antiogenesis, invasion/metastasis and wound healing(Immunol. Today 21(6) p. 260-4 (2000) by Wyman et al.; Science 287(5455)p. 1049-53 (2000) by Hirsch et al.; FASEB J. 15(11) p. 2019-21 (2001) byHirsch et al. and Nat. Immunol. 2(2) p. 108-15 (2001) by Gerard et al.).

Advances using genetic approaches and pharmacological tools haveprovided insights into signalling and molecular pathways that mediatechemotaxis in response to chemoattractant activated G-protein coupledreceptors. PI3-Kinase, responsible for generating these phosphorylatedsignalling products, was originally identified as an activity associatedwith viral oncoproteins and growth factor receptor tyrosine kinases thatphosphorylates phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al.,Trends Cell Biol. 2 p. 358-60 (1992)). However, more recent biochemicalstudies revealed that class I PI3 kinases (e.g. class IB isoform PI3Kγ)are dual-specific kinase enzymes, meaning they display both lipid kinaseand protein kinase activity, shown to be capable of phosphorylation ofother proteins as substrates, as well as auto-phosphorylation as anintra-molecular regulatory mechanism.

PI3-kinase activation, is therefore believed to be involved in a rangeof cellular responses including cell growth, differentiation, andapoptosis (Parker et al., Current Biology, 5 p. 577-99 (1995); Yao etal., Science, 267 p. 2003-05 (1995)). PI3-kinase appears to be involvedin a number of aspects of leukocyte activation. A p85-associatedPI3-kinase activity has been shown to physically associate with thecytoplasmic domain of CD28, which is an important costimulatory moleculefor the activation of T-cells in response to antigen (Pages et al.,Nature, 369 p. 327-29 (1994); Rudd, Immunity 4 p. 527-34 (1996)).Activation of T cells through CD28 lowers the threshold for activationby antigen and increases the magnitude and duration of the proliferativeresponse. These effects are linked to increases in the transcription ofa number of genes including interleukin-2 (IL2), an important T cellgrowth factor (Fraser et al., Science 251 p. 313-16 (1991)). Mutation ofCD28 such that it can no longer interact with PI3-kinase leads to afailure to initiate IL2 production, suggesting a critical role forPI3-kinase in T cell activation. PI3Kγ has been identified as a mediatorof G beta-gamma-dependent regulation of JNK activity, and G beta-gammaare subunits of heterotrimeric G proteins (Lopez-Ilasaca et al., J.Biol. Chem. 273(5) p. 2505-8 (1998)). Cellular processes in which PI3Ksplay an essential role include suppression of apoptosis, reorganizationof the actin skeleton, cardiac myocyte growth, glycogen synthasestimulation by insulin, TNFα-mediated neutrophil priming and superoxidegeneration, and leukocyte migration and adhesion to endothelial cells.

Recently, (Laffargue et al., Immunity 16(3) p. 441-51 (2002)) it hasbeen described that PI3Kγ relays inflammatory signals through variousG(i)-coupled receptors and its central to mast cell function, stimuli incontext of leukocytes, immunology includes cytokines, chemokines,adenosines, antibodies, integrins, aggregation factors, growth factors,viruses or hormones for example (J. Cell. Sci. 114(Pt 16) p. 2903-10(2001) by Lawlor et al.; Laffargue et al., 2002, above and Curr. OpinionCell Biol. 14(2) p. 203-13 (2002) by Stephens et al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin (cf. hereinafter), have been widelyused as PI3-kinase inhibitors. These compounds are non-specific PI3Kinhibitors, as they do not distinguish among the four members of Class IPI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI3-kinases is about15-20 μM (Fruman et al., Ann. Rev. Biochem., 67, p. 481-507 (1998)),also 5-10 microM on CK2 protein kinase and some inhibitory activity onphospholipases. Wortmannin is a fungal metabolite which irreversiblyinhibits PI3K activity by binding covalently to the catalytic domain ofthis enzyme. Inhibition of PI3K activity by wortmannin eliminatessubsequent cellular response to the extracellular factor. For example,neutrophils respond to the chemokine fMet-Leu-Phe (FMLP) by stimulatingPI3K and synthesizing PtdIns (3, 4, 5)P₃. This synthesis correlates withactivation of the respirators burst involved in neutrophil destructionof invading microorganisms. Treatment of neutrophils with wortmanninprevents the fMLP-induced respiratory burst response (Thelen et al.,Proc. Natl. Acad. Sci. USA, 91, p. 4960-64 (1994)). Indeed, theseexperiments with wortmannin, as well as other experimental evidence,shows that PI3K activity in cells of hematopoietic lineage, particularlyneutrophils, monocytes, and other types of leukocytes, is involved inmany of the non-memory immune response associated with acute and chronicinflammation.

Based on studies using wortmannin, there is evidence that PI3-kinasefunction is also required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al., 1994, above).Moreover, it has been shown that wortmannin and LY294002 blockneutrophil migration and superoxide release. Cyclooxygenase inhibitingbenzofuran derivatives are disclosed by John M. Janusz et al., in J.Med. Chem. 1998; Vol. 41, No. 18.

It is now well understood that deregulation of onocogenes andtumour-suppressor genes contributes to the formation of malignanttumours, for example by way of increase cell growth and proliferation orincreased cell survival. It is also now known that signaling pathwaysmediated by the PI3K family have a central role in a number of cellprocesses including proliferation and survival, and deregulation ofthese pathways is a causative factor a wide spectrum of human cancersand other diseases (Katso et al., Annual Rev. Cell Dev. Biol. 2001, 17:615-617 and Foster et al., J. Cell Science, 2003, 116: 3037-3040).

Class I PI3K is a heterodimer consisting of a p110 catalytic subunit anda regulatory subunit, and the family is further divided into class Iaand Class Ib enzymes on the basis of regulatory partners and mechanismof regulation. Class la enzymes consist of three distinct catalyticsubunits (p110α, p110β, and p110δ) that dimerise with five distinctregulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with allcatalytic subunits being able to interact with all regulatory subunitsto form a variety of heterodimers. Class Ia PI3K are generally activatedin response to growth factor-stimulation of receptor tyrosine kinases,via interaction of the regulatory subunit SH2 domains with specificphospho-tyrosine residues of the activated receptor or adaptor proteinssuch as IRS-1. Small GTPases (ras as an example) are also involved inthe activation of PI3K in conjunction with receptor tyrosine kinaseactivation. Both p110α and p110β are constitutively expressed in allcell types, whereas p110δ expression is more restricted to leukocytepopulations and some epithelial cells. In contrast, the single Class Ibenzyme consists of a p110γ catalytic subunit that interacts with a p101regulatory subunit. Furthermore, the Class Ib enzyme is activated inresponse to G-protein coupled receptor (GPCR) systems and its expressionappears to be limited to leukocytes.

There is now considerable evidence indicating that Class Ia PI3K enzymescontribute to tumourigenesis in a wide variety of human cancers, eitherdirectly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer,2002, 2, 489-501). For example, the p110α subunit is amplified in sometumours such as those of the ovary (Shayesteh, et al., Nature Genetics,1999, 21: 99-102) and cervix (Ma et al., Oncogene, 2000, 19: 2739-2744).More recently, activating mutations within p110α (PIK3CA gene) have beenassociated with various other tumors such as those of the colon and ofthe breast and lung (Samuels, et al., Science, 2004, 304, 554).Tumor-related mutations in p85α have also been identified in cancerssuch as those of the ovary and colon (Philp et al., Cancer Research,2001, 61, 7426-7429). In addition to direct effects, it is believed thatactivation of Class Ia PI3K contributes to tumourigenic events thatoccur upstream in signaling pathways, for example by way ofligand-dependent or ligand-independent activation of receptor tyrosinekinases, GPCR systems or integrins (Vara et al., Cancer TreatmentReviews, 2004, 30, 193-204). Examples of such upstream signalingpathways include over-expression of the receptor tyrosine kinase Erb2 ina variety of tumors leading to activation of PI3K-mediated pathways(Harari et al., Oncogene, 2000, 19, 6102-6114) and over-expression ofthe oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Inaddition, Class Ia PI3Ks may contribute indirectly to tumourigenesiscaused by various downstream signaling events. For example, loss offunction of the PTEN tumor-suppressor phosphatase that catalysesconversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a verybroad range of tumors via deregulation of PI3K-mediated production ofPI(3,4,5)P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).Furthermore, augmentation of the effects of other PI3K-mediatedsignaling events is believed to contribute to a variety of cancers, forexample by activation of AKT (Nicholson and Andeson, Cellular Signaling,2002, 14, 381-395).

In addition to a role in mediating proliferative and survival signalingin tumor cells, there is also good evidence that class Ia PI3K enzymesalso contributes to tumourigenesis via its function in tumor-associatedstromal cells. For examples, PI3K signaling is known to play animportant role in mediating angiogenic events in endothelial cells inresponse to pro-angiogenic factors such as VEGF (abid et al.,Arterioscler, Thromb. Vasc. Biol., 2004, 24, 294-300). As Class I PI3Kenzymes are also involved in motility and migration (Sawyer, ExpertOpinion investing. Drugs, 2004, 13, 1-19), PI3K inhibitors areanticipated to provide therapeutic benefit via inhibition of tumor cellinvasion and metastasis.

SUMMARY OF THE INVENTION

This invention relates to novel compounds of Formula (I):

-   -   in which    -   R2 is an optionally substituted ring system selected from a        group consisting of: formula (II), (III), (IV), (V), (VI),        (VII), (VIII), (IX) and (X):

-   -   R1 is selected from a group consisting of: heterocycloalkyl,        substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl        and substituted heteroaryl; each R3 and R4 is independently        selected from: hydrogen, halogen, acyl, amino, substituted        amino, C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl,        substituted C3-7cycloalkyl, C3-7heterocycloalkyl, substituted        C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl,        substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,        substituted arylalkyl, arylcycloalkyl, substituted        arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl,        cyano, hydroxyl, alkoxy, nitro, acyloxy, and aryloxy;    -   n is 1-2;    -   X is C or N; Y is C, O, N or S;    -   and/or a pharmaceutically acceptable salt thereof,    -   provided that in each of formula (V) to (X) at least one X or Y        is not carbon; further provided that R2 is not quinoline or        substituted quinoline.    -   R3 can be attached to any one of the four open carbon positions.

Suitably, this invention relates to a compound of formula (I) or apharmaceutically acceptable salt thereof.

Suitably, this invention relates to a method of treating cancer, whichcomprises administering to a subject in need thereof an effective amountof a compound of Formula (I).

Suitably, this invention relates to a method of treating one or moredisease states selected from: autoimmune disorders, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,asthma, pancreatitis, multiorgan failure, kidney diseases, plateletaggregation, sperm motility, transplantation rejection, graft rejectionand lung injuries, which comprises administering to a subject in needthereof an effective amount of a compound of Formula (I).

Included in the present invention are methods of co-administering thepresent PI3 kinase inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

Present compounds of Formula (I) inhibit one or more PI3 kinases.Suitably, the compounds of formula (I) inhibit PI3Kα. Also, compoundswithin the scope of this invention inhibit one or more PI3 kinasesselected from: PI3Kδ, PI3Kβ and PI3Kγ.

Suitably, this invention relates to novel compounds of Formula (I)(A):

-   -   in which    -   R2 is an optionally substituted ring system selected from a        group consisting of: formula (II), (III), and (IV) as defined        above;    -   R1 is selected from a group consisting of: heterocycloalkyl,        substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl        and substituted heteroaryl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,        alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,        substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,        acyloxy, and aryloxy;    -   n is 1-2;    -   X is C or N; Y is C, O, N or S;    -   and/or a pharmaceutically acceptable salt thereof;

Suitably, included among the presently invented compounds of formula (I)are those of formula (I)(B),

-   -   wherein R2 is selected from a group consisting of: formula        (V), (VI) and (IX) as defined above;    -   R1 is selected from a group consisting of: heterocycloalkyl,        substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl        and substituted heteroaryl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,        alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,        substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,        acyloxy, and aryloxy;    -   n is 1-2;    -   X is C or N; Y is C, O, N or S;    -   and/or a pharmaceutically acceptable salt thereof,    -   provided that in each of formula (V), (VI) and (IX) at least one        X or Y is not carbon.

Suitably, included among the presently invented compounds of formula (I)are those of formula (I)(C),

-   -   wherein R2 is selected from a group consisting of: formula        (VII), (VIII) and (X) as defined above;    -   R1 is selected from a group consisting of: heterocycloalkyl,        substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl        and substituted heteroaryl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,        alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,        substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,        acyloxy, and aryloxy;    -   n is 1-2;    -   X is C or N; Y is C, O, N or S;    -   and/or a pharmaceutically acceptable salt thereof,    -   provided that in each of formula (VII), (VIII) and (X) at least        one X or Y is not carbon.

Suitably, included among the presently invented compounds of formula (I)are those of formula (I)(D):

-   -   in which    -   R2 is an optionally substituted ring system selected from a        group consisting of: formula (II), (III), (IV), (V), (VI), and        (VIII):

-   -   R1 is selected from a group consisting of: heterocycloalkyl,        substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl        and substituted heteroaryl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl,        alkylcarboxy, aminoalkyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl,        substituted heteroarylalkyl, cyano, hydroxyl, alkoxy, nitro,        acyloxy, and aryloxy;    -   n is 1-2;    -   X is C or N; Y is C, O, N or S;    -   and/or a pharmaceutically acceptable salt thereof,    -   provided that in each of formula (V), (VI) and (VIII) at least        one X or Y is not carbon.

Suitably, among the present invention are compounds of Formula (I)(D),wherein R1 is heteroaryl or substituted heteroaryl; R2 is selected froma group consisting of: formula (III) and formula (VI).

Suitably, among the present invention are compounds of Formulas (I),(I)(A), (I)(B), (I)(C) and (I)(D), wherein R2 is pyridinyl orsubstituted pyridinyl.

Suitably, among the present invention are compounds of Formulas (I),(I)(A), (I)(B), (I)(C) and (I)(D), wherein R2 is not pyridinyl orsubstituted pyridinyl.

Suitably, among the present invention are compounds of Formula (I)wherein R2 is an optionally substituted ring system selected from thegroup consisting of Formulas (V)(A), (VI)(A), (VI)(B) and (IX)(A):

-   -   wherein X is C or N; Y is C, O, N or S;

Suitably, among the present invention are compounds of Formula (I)wherein R2 is an optionally substituted ring system selected from thegroup consisting of Formulas (VII)(A), (VIII)(A) and (X)(A):

-   -   wherein X is C or N; Y is C, O, N or S; provided that at least        one Y is not carbon.

Suitably, this invention relates to novel compounds of Formula (I)(G):

-   -   in which    -   each R1, R3, R4 and R5 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, arylamino, acylamino,        heterocycloalkylamino,    -   C1-6alkyl, substituted C1-6alkyl, C3-7cycloalkyl, substituted        C3-7cycloalkyl, C3-7heterocycloalkyl, substituted        C3-7heterocycloalkyl, alkylcarboxy, aminoalkyl, aryl,        substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,        substituted arylalkyl, arylcycloalkyl, substituted        arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl,        cyano, hydroxyl, alkoxy, acyloxy, and aryloxy; or R5 is R6,        wherein R6 is —SO2NR80 or —NSO₂R80, in which R80 is selected        from a group consisting of: C1-C6alkyl, C1-C6cycloalkyl,        C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted        C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl        optionally fused with a five-membered ring or substituted with        one to five groups selected from a group consisting of:        C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH, wherein n is 0-2,    -   n is 0-2, m is 0-3;    -   or a pharmaceutically acceptable salt thereof, Suitably, this        invention relates to novel compounds of Formula (I)(H):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano,        hydroxyl and alkoxy;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano,        hydroxyl and alkoxy;    -   or R5 is R6, wherein R6 is —SO2NR80 or —NSO₂R80, in which R80 is        selected from a group consisting of: C1-C6alkyl,        C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl,        substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl,        aryl optionally fused with a five-membered ring or substituted        with one to five groups selected from a group consisting of:    -   C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH, wherein n is 0-2,    -   n is 0-2, m is 0-2;    -   or a pharmaceutically acceptable salt thereof,

Suitably, this invention relates to novel compounds of Formula (I)(J):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R3 and R4 is independently selected from: hydrogen,        halogen, acyl, amino, substituted amino, C1-6alkyl, substituted        C1-6alkyl, C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano,        hydroxyl and alkoxy;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        C3-7cycloalkyl, substituted C3-7cycloalkyl,        C3-7heterocycloalkyl, substituted C3-7heterocycloalkyl, cyano,        hydroxyl, alkoxy, nitro;    -   R6 is —SO2NR80 or —NSO₂R80, in which R80 is selected from a        group consisting of: C1-C6alkyl, C1-C6cycloalkyl,        C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted        C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl        optionally fused with a five-membered ring or substituted with        one to five groups selected from a group consisting of:        C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH, wherein n is 0-2;    -   n is 0-2, m is 0-2;    -   or a pharmaceutically acceptable salt thereof.

Suitably, this invention relates to novel compounds of Formula (I)(K):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        cyano, hydroxyl, alkoxy;    -   n is 0-2, m is 0-1;    -   R6 is —SO2NR80 or —NSO₂R80, in which R80 is selected from a        group consisting of: C1-C6alkyl, C1-C6cycloalkyl,        C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted        C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl        optionally fused with a five-membered ring or substituted with        one to five groups selected from a group consisting of:        C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH, wherein n is 0-2;    -   or a pharmaceutically acceptable salt thereof.

Suitably, this invention relates to novel compounds of Formula (I)(L):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        cyano, hydroxyl, alkoxy;    -   R6 is —SO2NR80 or —NSO₂R80, wherein R80 is selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl,        C1-C6heterocycloalkyl, substituted C1-C6alkyl, substituted        C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl, aryl        optionally fused with a five-membered ring or substituted with        one to five groups selected from a group consisting of:        C1-C6alkyl, C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH;    -   n is 0-2, m is 0-1;    -   or a pharmaceutically acceptable salt thereof.

Suitably, this invention relates to novel compounds of Formula (I)(M):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        cyano, hydroxyl, alkoxy;    -   R6 is —NSO₂R80, wherein R80 is selected from a group consisting        of: C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl,        substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted        C1-C6heterocycloalkyl, aryl optionally fused with a        five-membered ring or substituted with one to five groups        selected from a group consisting of: C1-C6alkyl,        C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH; n is 0-2, m is 0-1;    -   or a pharmaceutically acceptable salt thereof.

Suitably, this invention relates to novel compounds of Formula (I)(N):

-   -   in which    -   R1 is selected from a group consisting of: heteroaryl,        substituted heteroaryl, heterocycloalkyl, substituted        heterocycloalkyl, amino, substituted amino, arylamino,        acylamino, heterocycloalkylamino, alkoxy, C1-6alkyl and        substituted C1-6alkyl;    -   each R5 is independently selected from: hydrogen, halogen, acyl,        amino, substituted amino, C1-6alkyl, substituted C1-6alkyl,        cyano, hydroxyl, alkoxy;    -   R6 is —SO2NR80, wherein R80 is selected from a group consisting        of: C1-C6alkyl, C1-C6cycloalkyl, C1-C6heterocycloalkyl,        substituted C1-C6alkyl, substituted C1-C6cycloalkyl, substituted        C1-C6heterocycloalkyl, aryl optionally fused with a        five-membered ring or substituted with one to five groups        selected from a group consisting of: C1-C6alkyl,        C1-C6cycloalkyl, halogen, amino, substituted amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo or —(CH₂)_(n)COOH,        or heteroaryl optionally fused with a five-membered ring or        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or        —(CH₂)_(n)COOH;    -   n is 0-2, m is 0-1    -   or a pharmaceutically acceptable salt thereof.    -   Suitably, this invention relates to compounds of Formulas (I)M)        and (I)(N), wherein R1 is selected from the group consisting of:        optionally substituted piperazine, optionally substituted        pyridazine, optionally substituted morphline, optionally        substituted pyrazole, substituted amino and optionally        substituted piperidine.    -   Suitably, this invention relates to compounds of Formulas (I)M)        and (I)(N), wherein R1 is selected from the group consisting of:        optionally substituted piperazine, optionally substituted        pyridazine, optionally substituted morphline, optionally        substituted pyrazole, substituted amino and optionally        substituted piperidine;    -   R80 is selected from a group consisting of: C1-C6alkyl,        C1-C6cycloalkyl, C1-C6heterocycloalkyl, substituted C1-C6alkyl,        substituted C1-C6cycloalkyl, substituted C1-C6heterocycloalkyl,        aryl and substituted aryl.    -   Suitably, this invention relates to compounds of Formulas (I) M)        and (I)(N), wherein R1 is selected from the group consisting of:        optionally substituted piperazine, optionally substituted        pyridazine, optionally substituted morphline, optionally        substituted pyrazole, substituted amino and optionally        substituted piperidine;    -   R80 is selected from a group consisting of: aryl optionally        substituted with one to five groups selected from a group        consisting of: C1-C6alkyl, C1-C6cycloalkyl, halogen, amino,        substituted amino, trifluoromethyl, cyano, hydroxyl, alkoxy, oxo        or —(CH₂)_(n)COOH, or heteroaryl optionally substituted with one        to five groups selected from a group consisting of: C1-C6alkyl,        C1-C6cycloalkyl, halogen, amino, trifluoromethyl, cyano,        hydroxyl, alkoxy, oxo, or —(CH₂)_(n)COOH; n is 0-2.    -   Suitably, this invention relates to the compound defined in        formula (I), (I)(A), (I)(B), (I)(C), (I) D), (I)(E), (I)(F),        (I)(G), (I)(H), (I)(J), (I)(K), (I)(M) or (I)(N).    -   Suitably, among the present invention are compounds selected        from a group consisting of:

-   5-[4-(4-pyridinyl)-6-quinolinyl]-1H-indazol-3-amine;

-   4,4′-di-4-pyridinyl-6,6′-biquinoline;

-   3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   2-amino-N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-(1H-tetrazol-5-yl)-2-pyridinamine;

-   6-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;

-   6-(1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;

-   3-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   2-amino-N-ethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-[2-(dimethylamino)ethyl]-N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-(3-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-3-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-(3-hydroxypropyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   3-(1-piperazinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   3-{[4-(methylsulfonyl)-1-piperazinyl]sulfonyl}-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-N-[3-(1-pyrrolidinyl)propyl]-3-pyridinesulfonamide;

-   3-[(3-amino-1H-pyrazol-1-yl)sulfonyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   3-[(4-methyl-1-piperazinyl)sulfonyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   2-[4-{2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-1-piperazinyl]ethanol;

-   2-amino-N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-2-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-4-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   3-{[4-(2-chlorophenyl)-1-piperazinyl]sulfonyl}-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   2-amino-N-[2-(methyloxy)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N,N-dimethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   N-methyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   N-ethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   N,N-diethyl-3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   6-[6-(ethyloxy)-5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[6-(methyloxy)-5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   3-methyl-7-[4-(4-pyridinyl)-6-quinolinyl]-2H-1,2,4-benzothiadiazine    1,1-dioxide;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-3,4-dihydro-1(2H)-isoquinolinone;

-   4-(4-pyridinyl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline;

-   6-(1H-indazol-5-yl)-4-(4-pyridinyl)quinoline;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-1H-indazol-3-amine;

-   4-(4-pyridinyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)quinoline;

-   6-(1H-indazol-6-yl)-4-(4-pyridinyl)quinoline;

-   {3-oxo-6-[4-(4-pyridinyl)-6-quinolinyl]-2,3-dihydro-1H-isoindol-1-yl}acetic    acid;

-   4-(4-pyridinyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)quinoline;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

-   6-[4-(4-pyridinyl)-6-quinolinyl][1,3]oxazolo[4,5-b]pyridin-2(3H)-one;

-   6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4-pyridinyl)quinoline;

-   4-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline;

-   6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;

-   6-(1-oxido-3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   4-(4-pyridinyl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-amine;

-   6-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-(4-pyridinyl)quinoline;

-   2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}propanamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}acetamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}methanesulfonamide;

-   2-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}acetamide;

-   6-pyrazolo[1,5-a]pyrimidin-6-yl-4-(4-pyridinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one;

-   6-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-(4-pyridinyl)quinoline;

-   6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(4-pyridinyl)quinoline;

-   3-[6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4-quinolinyl]benzenesulfonamide;

-   7-[4-(4-pyridinyl)-6-quinolinyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;

-   4-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one;

-   2-amino-N,N-dimethyl-5-[2-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-5-[8-fluoro-4-(4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-5-[7-fluoro-4-(4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-3-pyridinesulfonamide;

-   5-[5-fluoro-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[7-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[5-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   4-(4-pyridinyl)-6-[5-(trifluoromethyl)-3-pyridinyl]quinoline;    (4,6-di-4-pyridinylquinoline;

-   6-(3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   6-(2-pyridinyl)-4-(4-pyridinyl)quinoline;

-   6-(2,1,3-benzoxadiazol-5-yl)-4-(4-pyridinyl)quinoline;

-   6-(2,1,3-benzothiadiazol-5-yl)-4-(4-pyridinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;

-   2-ethyl-6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-pyrimidinone;

-   7-[4-(4-pyridinyl)-6-quinolinyl]-2-quinoxalinol;

-   2-(4-morpholinyl)-7-[4-(4-pyridinyl)-6-quinolinyl]quinoxaline;

-   4-(4-morpholinyl)-6-[4-(4-pyridinyl)-6-quinolinyl]quinazoline;

-   1-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;

-   1-(3-methylphenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;

-   1-(3-chlorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;

-   1-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one;

-   N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   6-(1H-indol-5-yl)-4-(4-pyridinyl)quinoline;

-   6-(1H-indol-6-yl)-4-(4-pyridinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-indol-2-one;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-1,3-dihydro-2H-indol-2-one;

-   7-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-quinazolinone;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-quinazolinone;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-1,2-benzisothiazol-3(2H)-one    1,1-dioxide;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-1,8-naphthyridin-2(1H)-one;

-   6-(1,3-benzoxazol-5-yl)-4-(4-pyridinyl)quinoline;

-   7-[4-(4-pyridinyl)-6-quinolinyl]-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

-   3-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinecarboxamide;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine;

-   4-[4-(4-pyridinyl)-6-quinolinyl]thieno[2,3-c]pyridine-2-carboxamide;

-   methyl    4-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxylate;

-   4-[4-(4-pyridinyl)-6-quinolinyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxamide;

-   6-(1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline;

-   6-(1H-imidazo[4,5-c]pyridin-2-yl)-4-(4-pyridinyl)quinoline;

-   6-(1H-imidazo[4,5-b]pyridin-2-yl)-4-(4-pyridinyl)quinoline;

-   6-(1H-purin-8-yl)-4-(4-pyridinyl)quinoline;

-   6-imidazo[1,2-a]pyridin-6-yl-4-(4-pyridinyl)quinoline;

-   6-imidazo[1,2-a]pyrimidin-6-yl-4-(4-pyridinyl)quinoline;

-   1-{6-[4-(4-pyridinyl)-6-quinolinyl]imidazo[1,2-a]pyridin-3-yl}-1-propanone;

-   6-(4-pyridazinyl)-4-(4-pyridinyl)quinoline;

-   1-{6-[4-(4-pyridinyl)-6-quinolinyl]imidazo[1,2-a]pyridin-3-yl}-1-propanol;

-   4-(1-piperidinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;

-   4-(4-morpholinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;

-   4-(4-methyl-1-piperazinyl)-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoline;

-   4-(4-pyridazinyl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinoline;

-   6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(1-piperidinyl)quinoline;

-   6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(4-morpholinyl)quinoline;

-   2-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-(4-phenyl-6-quinolinyl)-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-[4-(1H-pyrazol-3-yl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-5-[4-(2,6-dimethyl-4-pyridinyl)-6-quinolinyl]-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-5-(4-{3-[(aminosulfonyl)methyl]phenyl}-6-quinolinyl)-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-5-[4-(3-cyanophenyl)-6-quinolinyl]-N,N-dimethyl-3-pyridinesulfonamide;

-   2-amino-5-{4-[5-(aminosulfonyl)-3-pyridinyl]-6-quinolinyl}-N,N-dimethyl-3-pyridinesulfonamide;

-   5,5′-(4,6-quinolinediyl)di(3-pyridinesulfonamide);

-   2-amino-N,N-dimethyl-5-[4-(3-{[(1-methylethyl)amino]sulfonyl}phenyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-(4-{3-[(methylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinesulfonamide;

-   2-amino-N,N-dimethyl-5-{4-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-[4-(3-cyanophenyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-{4-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-[4-(2,6-dimethyl-4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinesulfonamide;

-   5-[4-(1-methyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-{4-[2-(4-morpholinylmethyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-{4-[2-(4-morpholinylcarbonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-{4-[2-(4-morpholinyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   4′-(4-pyridinyl)-3,4-dihydro-6,6′-biquinolin-2(1H)-one;

-   6-[4-(4-pyridinyl)-6-quinolinyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one;

-   2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbaldehyde;

-   {2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methyl    acetate;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-2,3-pyridinediamine;

-   2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;

-   6-[4-(4-pyridinyl)-6-quinolinyl]pyrido[2,3-d]pyrimidin-4(1H)-one;

-   5-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1,2-dihydro-3H-pyrazol-3-one;

-   7-[4-(4-pyridinyl)-6-quinolinyl]pyrido[3,2-d]pyrimidin-4(1H)-one;

-   6-[5-(1H-pyrazol-5-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   N-(2,4-difluorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;

-   6-[2-(methyloxy)-4-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[6-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   4-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinol;

-   6-[2-(methyloxy)-5-pyrimidinyl]-4-(4-pyridinyl)quinoline;

-   {6-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}methanol;

-   6-(2-chloro-4-pyridinyl)-4-(4-pyridinyl)quinoline;

-   4-(4-pyridinyl)-6-(5-pyrimidinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-2(1H)-pyrimidinone;

-   6-[2,6-bis(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[6-(4-morpholinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-(6-chloro-3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   6-[6-(ethyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   N,N-dimethyl-3-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}oxy)-1-propanamine;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;

-   methyl 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinecarboxylate;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}acetamide;

-   N-[2-(4-morpholinyl)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine;

-   6-[6-(1-piperazinyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[5-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-(6-fluoro-3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyrimidinecarbonitrile;

-   6-[2-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbonitrile;

-   6-[6-(methyloxy)-2-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[5-(4-morpholinylcarbonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[4-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[5-(4-morpholinylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   7-[4-(4-pyridinyl)-6-quinolinyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarbaldehyde;

-   6-(4-chloro-3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   4-(4-pyridinyl)-6-[5-(1H-tetrazol-5-yl)-3-pyridinyl]quinoline;

-   N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N,N-dimethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   6-[4-methyl-6-(methyloxy)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   N-{4-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}acetamide;

-   6-(4-methyl-3-pyridinyl)-4-(4-pyridinyl)quinoline;

-   6-[5-(1,3,4-oxadiazol-2-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   2-amino-N-(4-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N,N-diethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-3-(1-pyrrolidinylsulfonyl)-2-pyridinamine;

-   2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-N-[2-(1-pyrrolidinyl)ethyl]-3-pyridinesulfonamide;

-   6-[6-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   2-amino-N-(phenylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-(2-hydroxyethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   1-({2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-4-piperidinol;

-   2-amino-N-(2-aminoethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   6-[5-(methylthio)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   6-[5-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   2-amino-N-(2-hydroxyethyl)-N-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-cyclopropyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2-amino-N-1,3-benzodioxol-5-yl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N,N-diethyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   1-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfonyl)-4-piperidinol;

-   4-(4-pyridinyl)-6-[5-(1-pyrrolidinylsulfonyl)-3-pyridinyl]quinoline;

-   N-(2-hydroxyethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-(phenylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   5-[4-(4-pyridinyl)-6-quinolinyl]-N-[2-(1-pyrrolidinyl)ethyl]-3-pyridinesulfonamide;

-   6-{5-[(4-methyl-1-piperazinyl)sulfonyl]-3-pyridinyl}-4-(4-pyridinyl)quinoline;

-   N-cyclopropyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-[2-(methyloxy)ethyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-1,3-benzodioxol-5-yl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-(3-pyridinylmethyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-2-pyridinyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-(2-chlorophenyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-cyclohexyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-[2-(methyloxy)phenyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   2,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazole-4-sulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiophenesulfonamide;

-   3,5-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-4-isoxazolesulfonamide;

-   3,4-bis(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1-propanesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropanesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;    and

-   1-phenyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanesulfonamide;

-   5-{4-[3-chloro-4-(methyloxy)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide;

-   5-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-6-quinolinyl}-3-pyridinesulfonamide;

-   N-(cyclopropylsulfonyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropanesulfonamide;

-   N-(2,4-difluorophenyl)-5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-methyl-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-(2,4-difluorophenyl)-5-(4-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-6-quinolinyl)-3-pyridinesulfonamide;

-   N-(2,4-difluorophenyl)-5-[4-(4-isoquinolinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   N-phenyl-N′-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}urea;

-   2-{4-[6-(5-{[(2,4-difluorophenyl)amino]sulfonyl}-3-pyridinyl)-4-quinolinyl]-1H-pyrazol-1-yl}acetamide;

-   N-{5-[4-(1-methyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   4′-(4-pyridinyl)-3,6′-biquinoline;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzamide;

-   5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-N-(2,4-difluorophenyl)-3-pyridinesulfonamide;

-   6-[5-(1H-pyrazol-4-yl)-3-pyridinyl]-4-(4-pyridinyl)quinoline;

-   N,N-diethyl-2-oxo-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3-pyridinesulfonamide;

-   4-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-methyl-N-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinecarboxamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}ethanesulfonamide;

-   4-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   4-(1-methylethyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine;

-   4-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}-2,4-difluorobenzenesulfonamide;

-   1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-H-pyrazole-3-sulfonamide;

-   2-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-cyano-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2-methyl-5-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyrazole-4-sulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-methyl-5-nitrobenzenesulfonamide;

-   N-{2-chloro-5-[4-(1-ethyl-1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   3-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinyl}benzenesulfonamide;

-   2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2,4-difluoro-N-{5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   5-fluoro-2-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-nitrobenzenesulfonamide;

-   N-{2-chloro-5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-methylbenzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-fluorobenzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiophenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropanesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-5-fluoro-2-methylbenzenesulfonamide;

-   N-(2-chloro-5-{4-[3-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl)benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3,5-dimethyl-4-isoxazolesulfonamide;

-   2,4-difluoro-N-(5-{4-[3-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl)benzenesulfonamide;

-   2,4-difluoro-N-{5-[4-(2-methyl-4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   3-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-[4-(cyanomethyl)phenyl]-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide;

-   3-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2,4-difluorobenzenesulfonamide;

-   3-nitro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-3-pyridinyl}-2,4-difluorobenzenesulfonamide;

-   3-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-4-(trifluoromethyl)benzenesulfonamide;

-   N-{2-hydroxy-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-(trifluoromethyl)benzenesulfonamide;

-   N-{5-[4-(1-benzofuran-2-yl)-6-quinolinyl]-2-chloro-3-pyridinyl}benzenesulfonamide;

-   N-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzamide;

-   2,4-difluoro-N-{5-[4-(4-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2,4-difluoro-N-[5-(4-pyrazolo[1,5-a]pyridin-3-yl-6-quinolinyl)-3-pyridinyl]benzenesulfonamide;

-   2,4-difluoro-N-{5-[4-(2-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2,4-difluoro-N-(5-{4-[4-(trifluoromethyl)phenyl]-6-quinolinyl}-3-pyridinyl)benzenesulfonamide;

-   2,4-difluoro-N-(5-{4-[4-(methylsulfonyl)phenyl]-6-quinolinyl}-3-pyridinyl)benzenesulfonamide;

-   methyl    1-methyl-5-[{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}amino)sulfonyl]-1H-pyrrole-2-carboxylate;

-   5-bromo-2-(methyloxy)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   5-(5-isoxazolyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-thiophenesulfonamide;

-   2,4-difluoro-N-{5-[4-(3-fluorophenyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   2,4-difluoro-N-(5-{4-[3-(trifluoromethyl)phenyl]-6-quinolinyl}-3-pyridinyl)benzenesulfonamide;

-   2-chloro-4-cyano-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-[5-(4-{3-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinyl]-2,4-difluorobenzenesulfonamide;

-   N-[5-(4-{4-[(dimethylamino)sulfonyl]phenyl}-6-quinolinyl)-3-pyridinyl]-2,4-difluorobenzenesulfonamide;

-   1,2-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazole-4-sulfonamide;

-   3-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinolinyl]benzamide;

-   4-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinolinyl]benzamide;

-   N-{4-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinolinyl]phenyl}acetamide;

-   N-{3-[6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-3-pyridinyl)-4-quinolinyl]phenyl}acetamide;

-   6-(4-morpholinyl)-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-pyridinesulfonamide;

-   2-fluoro-4-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-furansulfonamide;

-   1,3-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyrazole-4-sulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-(trifluoromethyl)benzenesulfonamide;

-   N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclohexanesulfonamide;

-   N-[5-(4-cyclopentyl-6-quinolinyl)-2-(methyloxy)-3-pyridinyl]benzenesulfonamide;

-   2,5-dichloro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   3-cyano-4-fluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1-pyrrolidinesulfonamide;

-   (5Z)-5-({5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methylidene)-1,3-thiazolidine-2,4-dione;

-   N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}cyclopropanesulfonamide;

-   N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-2-pyridinesulfonamide;

-   1,2-dimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-imidazole-5-sulfonamide;

-   1-methyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide;

-   1,3,5-trimethyl-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}-1H-pyrazole-4-sulfonamide;

-   N-{2-(ethyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N,N-dimethyl-N′-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}sulfamide;

-   N-{2-chloro-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}-2,4-difluorobenzenesulfonamide;

-   N-{2-chloro-1-oxido-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{6-methyl-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;

-   N-{2-(methyloxy)-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanesulfonamide;

-   N-{2-chloro-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}methanesulfonamide;

-   2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide;    and/or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating cancer, whichcomprises co-administering to a subject in need thereof an effectiveamount of a compound of Formula (I), and/or a pharmaceuticallyacceptable salt thereof, and at least one anti-neoplastic agent such asone selected from the group consisting of: anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Ihinibitors, hormones and hormonal anlogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, and cell cycle signalinginhibitors.

This invention also relates to a method of treating cancer, whichcomprises co-administering to a subject in need thereof an effectiveamount of a compound of Formula (I), and/or a pharmaceuticallyacceptable salt thereof; and at least one signal transduction pathwayinhibitor such as one selected from the group consisting of: receptortyrosine kinase inhibitor, non-receptor tyrosine kinase inhibitor,SH2/SH3 domain blocker, serine/threonine kinase inhibitor, phosphotidylinositol-3 kinase inhibitor, myo-inositol singaling inhibitor, and Rasoncogene inhibitor.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

Compounds of Formula (I) are included in the pharmaceutical compositionsof the invention.

DEFINITIONS

By the term “substituted amino” as used herein, is meant —NR30R40wherein each R30 and R40 is independently selected from a groupincluding hydrogen, C1-6alkyl, acyl, C3-C7cycloalkyl, wherein at leastone of R30 and R40 is not hydrogen.

By the term “acyl” as used herein, unless otherwise defined, is meant—C(O)(alkyl), —C(O)(cycloalkyl), —C(O)(aryl) or —C(O)(heteroaryl),wherein heteroaryl and aryl are optionally substituted.

By the term “aryl” as used herein, unless otherwise defined, is meantaromatic, hydrocarbon, ring system. The ring system may be monocyclic orfused polycyclic (e.g. bicyclic, tricyclic, etc.). In variousembodiments, the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6,where these carbon numbers refer to the number of carbon atoms that formthe ring system. A C6 ring system, i.e. a phenyl ring is a suitable arylgroup. In various embodiments, the polycyclic ring is a bicyclic arylgroup, where suitable bicyclic aryl groups are C8-C12, or C9-C10. Anaphthyl ring, which has 10 carbon atoms, is a suitable polycyclic arylgroup.

By the term “heteroaryl” as used herein, unless otherwise defined, ismeant an aromatic ring system containing carbon(s) and at least oneheteroatom. Heteroaryl may be monocyclic or polycyclic. A monocyclicheteroaryl group may have 1 to 4 heteroatoms in the ring, while apolycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclicheteroaryl ring may contain fused, spiro or bridged ring junctions, forexample, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclicheteroaryl rings may contain from 8 to 12 member atoms. Monocyclicheteroaryl rings may contain from 5 to 8 member atoms (carbons andheteroatoms). Exemplary heteroaryl groups include but are not limitedto: benzofuran, benzothiophene, furan, imidazole, indole, isothiazole,oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,quinoline, quinazoline, quinoxaline, thiazole, and thiophene.

By the term “monocyclic heteroaryl” as used herein, unless otherwisedefined, is meant a monocyclic heteroaryl ring containing 1-5 carbonatoms and 1-4 hetero atoms.

By the term “alkylcarboxy” as used herein, unless otherwise defined, ismeant —(CH₂)_(n)COOR₈₀, wherein R80 is hydrogen or C1-C6alkyl, n is 0-6.

By the term “alkoxy” as used herein is meant —O(alkyl) including —OCH₃,—OCH₂CH₃ and —OC(CH₃)₃ where alkyl is as described herein.

By the term “alkylthio” as used herein is meant —S(alkyl) including—SCH₃, —SCH₂CH₃ where alkyl is as described herein.

The term “cycloalkyl” as used herein unless otherwise defined, is meanta nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12.

Examples of cycloalkyl and substituted cycloalkyl substituents as usedherein include: cyclohexyl, aminocyclohexyl, cyclobutyl,aminocyclobutyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl,propyl-4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl,cyclopropyl, aminocyclopentyl, and cyclopentyl.

By the term “heterocycloalkyl” as used herein is meant a non-aromatic,unsaturated or saturated, monocyclic or polycyclic, heterocyclic ringcontaining at least one carbon and at least one heteroatom. Exemplarymonocyclic heterocyclic rings include: piperidine, piperazine,pyrrolidine, and morpholine. Exemplary polycyclic heterocyclic ringsinclude quinuclidine.

By the term “substituted” as used herein, unless otherwise defined, ismeant that the subject chemical moiety has one to five substituents,suitably from one to three substituents selected from the groupconsisting of: hydrogen, halogen, C1-C6alkyl, amino, urea,trifluoromethyl, —(CH₂)_(n)COOH, C3-C7cycloalkyl, substituted amino,aryl, heteroaryl, arylalkyl, arylcycloalkyl, heteroarylalkyl,heterocycloalkyl, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy,acyl, acylamino, aminoacyl, arylamino, nitro, oxo, —CO₂R₅₀, —SO₂R₇₀,—NR₅₀SO₂R₇₀, NR₅₀C(O)R₇₅ and —CONR₅₅R₆₀, wherein R₅₀ and R₅₅ are eachindependently selected from: hydrogen, alkyl, and C3-C7cycloalkyl; R₅₅and R₆₀ can optionally form a heterocycloalkyl ring; n is 0 to 6; R₇₅ isselected from the group consisting of: C1-C6alkyl, C3-7cylcoalkyl,substituted C3-7cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, amino, substituted amino, arylamino,C1-C6heterocycloalkyl, alkoxy, aryloxy and substitutedC1-C6heterocycloalkyl; each R60 and R70 is independently selected fromthe group consisting of: C1-C6alkyl, C3-C7cycloalkyl, substitutedC1-C6heterocycloalkyl, C1-C6heterocycloalkyl, halogen, amino,substituted amino, arylamino, trifluoromethyl, cyano, hydroxyl, alkoxy,oxo, —(CH₂)_(n)COOH, aryl optionally fused with a five-membered ring orsubstituted with one to five groups selected from the group consistingof: C1-C6alkyl, C3-C7cycloalkyl, halogen, amino, substituted amino,trifluoromethyl, cyano, hydroxyl, alkoxy, oxo, or —(CH₂)_(n)COOH, orheteroaryl optionally fused with a five-membered ring or substitutedwith one to five groups selected from the group consisting of:C1-C6alkyl, C3-C7cycloalkyl, halogen, amino, trifluoromethyl, cyano,hydroxyl, alkoxy, oxo, or —(CH₂)_(n)COOH.

By the term “substituted”, when referred in the definition of R60, R70,R75, “arylamino”, and “aryloxy”, is meant that the subject chemicalmoiety has one to five substituents, suitably from one to three,selected from the group consisting of: hydrogen, C1-C6alkyl, halogen,trifluoromethyl, —(CH₂)_(n)COOH, amino, substituted amino, cyano,hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy, acyl, acylamino, andnitro, n is 0-6.

By the term “acyloxy” as used herein is meant —OC(O)alkyl where alkyl isas described herein. Examples of acyloxy substituents as used hereininclude: —OC(O)CH₃, —OC(O)CH(CH₃)₂ and —OC(O)(CH₂)₃CH₃.

By the term “acylamino” as used herein is meant —N(H)C(O)alkyl,—N(H)C(O)(cycloalkyl) where alkyl is as described herein. Examples ofN-acylamino substituents as used herein include: —N(H)C(O)CH₃,—N(H)C(O)CH(CH₃)₂ and —N(H)C(O)(CH₂)₃CH₃.

By the term “aminoacyl” as used herein is meant —C(O)N(alkyl)_(n),—C(O)N(cycloalkyl)_(n) where alkyl is as described herein, n is 1-2.

By the term “aryloxy” as used herein is meant —O(aryl), —O(substitutedaryl), —O(heteroaryl) or —O(substituted heteroaryl).

By the term “arylamino” as used herein is meant —NR₈₀(aryl),—NR₈₀(substituted aryl), —NR₈₀(heteroaryl) or —NR₈₀(substitutedheteroaryl), wherein R80 is H, C1-6alkyl or C3-C7cycloalkyl.

By the term “heteroatom” as used herein is meant oxygen, nitrogen orsulfur.

By the term “halogen” as used herein is meant a substituent selectedfrom bromide, iodide, chloride and fluoride.

By the term “alkyl” and derivatives thereof and in all carbon chains asused herein, including alkyl chains defined by the term “—(CH₂)_(n)”,“—(CH₂)_(m)” and the like, is meant a linear or branched, saturated orunsaturated hydrocarbon chain, and unless otherwise defined, the carbonchain will contain from 1 to 12 carbon atoms.

By the term “substituted alkyl” as used herein is meant an alkyl groupsubstituted with one to six substituents selected from the groupconsisting of: halogen, trifluoromethyl, alkylcarboxy, amino,substituted amino, cyano, hydroxyl, alkoxy, alkylthio, aryloxy, acyloxy,acyl, acylamino, carbamate, urea, sulfonamate, C3-7cycloheteralkyl,C3-7cycloalkyl and nitro.

Examples of alkyl and substituted alkyl substituents as used hereininclude: —CH₃, —CH₂—CH₃, —CH₂—CH₂—CH₃, —CH(CH₃)₂, —CH₂—CH₂—C(CH₃)₃,—CH₂—CF₃, —C≡C—C(CH₃)₃, —C≡C—CH₂—OH, cyclopropylmethyl,—CH₂—C(CH₃)₂—CH₂—NH₂, —C≡C—C₆H₅, —C≡C—C(CH₃)₂—OH,—CH₂—CH(OH)—CH(OH)—CH(OH)—CH(OH)—CH₂—OH, piperidinylmethyl,methoxyphenylethyl, —C(CH₃)₃, —(CH₂)₃—CH₃, —CH₂—CH(CH₃)₂,—CH(CH₃)—CH₂—CH₃, —CH═CH₂, and —C≡C—CH₃.

By the term “treating” and derivatives thereof as used herein, is meantprophylatic and therapeutic therapy. Prophylatic therapy is meant theinstitution of measures to protect a person from a disease to which heor she has been, or may be, exposed. Also called preventive treatment.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of a PI3 kinase inhibiting compound, asdescribed herein, and a further active ingredient or ingredients. Theterm further active ingredient or ingredients, as used herein, includesany compound or therapeutic agent known to or that demonstratesadvantageous properties when administered to a patient in need oftreatment. Suitably, if the administration is not simultaneous, thecompounds are administered in a close time proximity to each other.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered topically andanother compound may be administered orally.

The term “compound” as used herein includes all isomers of the compound.Examples of such isomers include: enantiomers, tautomers, rotamers.

In formula (V) to (X), when a “dot” bond is drawn between two atoms, itis meant that such bond can be either single or double bond. A ringsystem containing such bonds can be aromatic or non-aromatic.

Certain compounds described herein may contain one or more chiral atoms,or may otherwise be capable of existing as two enantiomers, or two ormore diastereoisomers. Accordingly, the compounds of this inventioninclude mixtures of enantiomers/diastereoisomers as well as purifiedenantiomers/diastereoisomers or enantiomerically/diastereoisomericallyenriched mixtures. Also included within the scope of the invention arethe individual isomers of the compounds represented by formula I or IIabove as well as any wholly or partially equilibrated mixtures thereof.The present invention also covers the individual isomers of thecompounds represented by the formulas above as mixtures with isomersthereof in which one or more chiral centers are inverted. Further, anexample of a possible tautomer is an oxo substituent in place of ahydroxy substituent. Also, as stated above, it is understood that alltautomers and mixtures of tautomers are included within the scope of thecompounds of Formula I or II.

Compounds of Formula (I) are included in the pharmaceutical compositionsof the invention. Where a —COOH or —OH group is present,pharmaceutically acceptable esters can be employed, for example methyl,ethyl, pivaloyloxymethyl, and the like for —COOH, and acetate maleateand the like for —OH, and those esters known in the art for modifyingsolubility or hydrolysis characteristics, for use as sustained releaseor prodrug formulations.

It has now been found that compounds of the present invention areinhibitors of the Phosphatoinositides 3-kinases (PI3Ks), particularlyPI3Kα. When the phosphatoinositides 3-kinase (PI3K) enzyme is inhibitedby a compound of the present invention, PI3K is unable to exert itsenzymatic, biological and/or pharmacological effects. The compounds ofthe present invention are therefore useful in the treatment ofautoimmune disorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, platelet aggregation, cancer, sperm motility,transplantation rejection, graft rejection and lung injuries,particularly cancer.

Compounds according to Formula (I) are suitable for the modulation,notably the inhibition of the activity of phosphatoinositide 3-kinases(PI3K), suitably phosphatoinositides 3-kinase (PI3Kα). Therefore thecompounds of the present invention are also useful for the treatment ofdisorders which are mediated by PI3Ks. Said treatment involves themodulation—notably the inhibition or the down regulation—of thephosphatoinositides 3-kinases.

Suitably, the compounds of the present invention are used for thepreparation of a medicament for the treatment of a disorder selectedfrom multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosis, inflammatory bowel disease, lung inflammation, thrombosisor brain infection/inflammation, such as meningitis or encephalitis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke orischemic conditions, cardiovascular diseases such as athero-sclerosis,heart hypertrophy, cardiac myocyte dysfunction, elevated blood pressureor vasoconstriction.

Suitably, the compounds of Formula (I) are useful for the treatment ofautoimmune diseases or inflammatory diseases such as multiple sclerosis,psoriasis, rheumatoid arthritis, systemic lupus erythematosis,inflammatory bowel disease, lung inflammation, thrombosis or braininfection/inflammation such as meningitis or encephalitis.

Suitably, the compounds of Formula (I) are useful for the treatment ofneurodegenerative diseases including multiple sclerosis, Alzheimer'sdisease, Huntington's disease, CNS trauma, stroke or ischemicconditions.

Suitably, the compounds of Formula (I) are useful for the treatment ofcardiovascular diseases such as atherosclerosis, heart hypertrophy,cardiac myocyte dysfunction, elevated blood pressure orvasoconstriction.

Suitably, the compounds of Formula (I) are useful for the treatment ofchronic obstructive pulmonary disease, anaphylactic shock fibrosis,psoriasis, allergic diseases, asthma, stroke, ischemic conditions,ischemia-reperfusion, platelets aggregation/activation, skeletal muscleatrophy/hypertrophy, leukocyte recruitment in cancer tissue,angiogenesis, invasion metastasis, in particular melanoma, Karposi'ssarcoma, acute and chronic bacterial and virual infections, sepsis,transplantation rejection, graft rejection, glomerulo sclerosis,glomerulo nephritis, progressive renal fibrosis, endothelial andepithelial injuries in the lung, and lung airway inflammation.

Because the pharmaceutically active compounds of the present inventionare active as PI3 kinase inhibitors, particularly the compounds thatinhibit PI3Kα, either selectively or in conjunction with one or more ofPI3Kδ, PI3Kβ, and/or PI3Kγ, they exhibit therapeutic utility in treatingcancer.

Suitably, the invention relates to a method of treating cancer in amammal, including a human, wherein the cancer is selected from: brain(gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast, inflammatory breast cancer,Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma,ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumorof bone and thyroid.

Suitably, the invention relates to a method of treating cancer in amammal, including a human, wherein the cancer is selected from:Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chroniclymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia, Chronic neutrophilic leukemia, Acutelymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cellleukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblasticleukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocyticleukemia and Erythroleukemia.

Suitably, the invention relates to a method of treating cancer in amammal, including a human, wherein the cancer is selected from:malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicularlymphoma.

Suitably, the invention relates to a method of treating cancer in amammal, including a human, wherein the cancer is selected from:neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvalcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor) and testicular cancer.

When a compound of Formula (I) is administered for the treatment ofcancer, the term “co-administering” and derivatives thereof as usedherein is meant either simultaneous administration or any manner ofseparate sequential administration of a PI3 kinase inhibiting compound,as described herein, and a further active ingredient or ingredients,known to be useful in the treatment of cancer, including chemotherapyand radiation treatment. The term further active ingredient oringredients, as used herein, includes any compound or therapeutic agentknown to or that demonstrates advantageous properties when administeredto a patient in need of treatment for cancer. Preferably, if theadministration is not simultaneous, the compounds are administered in aclose time proximity to each other. Furthermore, it does not matter ifthe compounds are administered in the same dosage form, e.g. onecompound may be administered topically and another compound may beadministered orally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof cancer in the present invention. Examples of such agents can be foundin Cancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; and cell cycle signaling inhibitors.

Examples of a further active ingredient or ingredients (anti-neoplasticagent) for use in combination or co-administered with the presentlyinvented AKT inhibiting compounds are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α1,4,7β,10,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem., Soc., 93:2325. 1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.Intem, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guides 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β, 13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate(NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine isindicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′], is commercially available asPARAPLATIN® as an injectable solution. Carboplatin is primarilyindicated in the first and second line treatment of advanced ovariancarcinoma. Bone marrow suppression is the dose limiting toxicity ofcarboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as aliposomal injectable form as DAUNOXOME® or as an injectable asCERUBIDINE®. Daunorubicin is indicated for remission induction in thetreatment of acute nonlymphocytic leukemia and advanced HIV associatedKaposi's sarcoma. Myelosuppression is the most common dose limiting sideeffect of daunorubicin.

Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leucopenia tends to be more severethan thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate,N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.Myelosuppression (leucopenia, thrombocytopenia, and anemia) andmucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectablesolution CAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I—DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I:DNA:irintecanor SN-38 ternary complex with replication enzymes. Irinotecan isindicated for treatment of metastatic cancer of the colon or rectum. Thedose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as theinjectable solution HYCAMTIN®. Topotecan is a derivative of camptothecinwhich binds to the topoisomerase I—DNA complex and prevents religationof singles strand breaks caused by Topoisomerase I in response totorsional strain of the DNA molecule. Topotecan is indicated for secondline treatment of metastatic carcinoma of the ovary and small cell lungcancer. The dose limiting side effect of topotecan HCl ismyelosuppression, primarily neutropenia.

Also of interest, is the camptothecin derivative of formula A following,currently under development, including the racemic mixture (R,S) form aswell as the R and S enantiomers:

known by the chemical name“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin(racemic mixture) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin(R enantiomer) or“7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin(S enantiomer). Such compound as well as related compounds aredescribed, including methods of making, in U.S. Pat. Nos. 6,063,923;5,342,947; 5,559,235; 5,491,237 and pending U.S. patent application Ser.No. 08/977,217 filed Nov. 24, 1997.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, androgens, and anti-androgens such asflutamide, nilutamide, bicalutamide, cyproterone acetate and5α-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagagonists suchas goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltranduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by over-expression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosinekinase with immunoglobulin-like and epidermal growth factor homologydomains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophagecolony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growthfactor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin(eph) receptors, and the RET protooncogene. Several inhibitors of growthreceptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C., Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997;and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed non-receptor tyrosine kinases. Non-receptor tyrosine kinases foruse in the present invention, which are targets or potential targets ofanti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S, and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domainbinding in a variety of enzymes or adaptor proteins including, PI3-K p85subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) andRas-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussedin Smithgall, T. E. (1995), Journal of Pharmacological and ToxicologicalMethods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase familymembers, and TGF beta receptor kinases. Such Serine/Threonine kinasesand inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment andResearch. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal ChemistryLetters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; andMartinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphotidyl inositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in thepresent invention. Such kinases are discussed in Abraham, R. T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also of interest in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancer:erbB Family ReceptorTyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2Activity by a monoclonal Anti-VEGF antibody blocks tumor growthin mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in thepresent invention. Inhibitors of angiogenesis related VEGFR and TIE2 arediscussed above in regard to signal transduction inhibitors (bothreceptors are receptor tyrosine kinases). Angiogenesis in general islinked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR havebeen shown to inhibit angiogenesis, primarily VEGF expression.Accordingly, non-receptor tyrosine kinase inhibitors may be used incombination with the compounds of the present invention. For example,anti-VEGF antibodies, which do not recognize VEGFR (the receptortyrosine kinase), but bind to the ligand; small molecule inhibitors ofintegrin (alpha_(v) beta₃) that will inhibit angiogenesis; endostatinand angiostatin (non-RTK) may also prove useful in combination with thedisclosed compounds. (See Bruns C J et al (2000), Cancer Res., 60:2926-2935; Schreiber A B, Winkler M E, and Derynck R. (1986), Science,232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of formula (I). There are a number ofimmunologic strategies to generate an immune response. These strategiesare generally in the realm of tumor vaccinations. The efficacy ofimmunologic approaches may be greatly enhanced through combinedinhibition of signaling pathways using a small molecule inhibitor.Discussion of the immunologic/tumor vaccine approach against erbB2/EGFRare found in Reilly R T et al. (2000), Cancer Res. 60: 3569-3576; andChen Y, Hu D, Eling D J, Robbins J, and Kipps T J. (1998), Cancer Res.58: 1965-1971.

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention. Members of the Bcl-2 family of proteins block apoptosis.Upregulation of bcl-2 has therefore been linked to chemoresistance.Studies have shown that the epidermal growth factor (EGF) stimulatesanti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore,strategies designed to downregulate the expression of bcl-2 in tumorshave demonstrated clinical benefit and are now in Phase II/III trials,namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptoticstrategies using the antisense oligonucleotide strategy for bcl-2 arediscussed in Water J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; andKitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

In one embodiment, the cancer treatment method of the claimed inventionincludes the co-administration a compound of formula I and/or apharmaceutically acceptable salt thereof and at least oneanti-neoplastic agent, such as one selected from the group consisting ofanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,and cell cycle signaling inhibitors.

Because the pharmaceutically active compounds of the present inventionare active as PI3 kinase inhibitors, particularly the compounds thatmodulate/inhibit PI3Kα, it is useful in treating cancer. Because thepharmaceutically active compounds of the present invention are alsoactive against one or more of PI3Kδ, PI3Kβ, and/or PI3Kγ, they exhibittherapeutic utility in treating a disease state selected from:autoimmune disorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, platelet aggregation, sperm motility,transplantation rejection, graft rejection and lung injuries.

When a compound of Formula (I) is administered for the treatment of adisease state selected from: autoimmune disorders, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,cancer, asthma, pancreatitis, multiorgan failure, kidney diseases,platelet aggregation, sperm motility, transplantation rejection, graftrejection or lung injuries, the term “co-administering” and derivativesthereof as used herein is meant either simultaneous administration orany manner of separate sequential administration of a PI3 kinaseinhibiting compound, as described herein, and a further activeingredient or ingredients, known to be useful in the treatment of suchautoimmune disorder, cancer, inflammatory diseases, cardiovasculardisease, neurodegenerative disease, allergy, asthma, pancreatitis,multiorgan failure, kidney diseases, platelet aggregation, spermmotility, transplantation rejection, graft rejection and/or lunginjuries.

Biological Assays

PI3K alpha Leadseeker SPA Assay

Compounds of the present invention were tested according to thefollowing assays and found as inhibitors of PI3 kinases, particularlyPI3Kα. The exemplified compounds were tested and found active againstPI3Kα. The IC₅₀'s ranged from about 1 nM to 10 μM. The majority of thecompounds were under 500 nM; the most active compounds were under 10 nM.

The compound of Example 249 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 1.6 nM against PI3Kα.

The compound of Example 252 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 0.8 nM against PI3Kα.

The compound of Example 263 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 7.9 nM against PI3Kα.

The compound of Example 289 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 2.5 nM against PI3Kα.

The compound of Example 154 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 316 nM against PI3Kα.

The compound of Example 156 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 79 nM against PI3Kα.

The compound of Example 224 was tested generally according to the assaysdescribed herein and in at least one experimental run exhibited a IC50value: equal to 1000 nM against PI3Kα.

Assay Principle

SPA imaging beads are microspheres containing scintillant which emitlight in the red region of the visible spectrum. As a result, thesebeads are ideally suited to use with a CCD imager such as the Viewlux.The Leadseeker beads used in this system are polystyrene beads that havebeen coupled with polyethyleneimine. When added to the assay mixture,the beads absorb both the substrate (PIP2) and product (PIP3). AdsorbedP³³-PIP3 will cause an increase in signal, measured as ADUs (analog todigital units). This protocol details the use of the PEI-PS Leadseekerbeads for assays using His-p110/p85 PI3K alpha.

Assay Protocol

Solid compounds are typically plated with 0.1 μl of 100% DMSO in allwells (except column 6 and 18) of a 384-well, flat bottom, low volumeplate (Greiner 784075). The compounds are serially diluted (3-fold in100% DMSO) across the plate from column 1 to column 12 and column 13 tocolumn 24 and leave column 6 and 18 containing only DMSO to yield 11concentrations for each test compound. The assay buffer contains MOPS(pH 6.5), CHAPS, and DTT. PI3K alpha and PIP2(L-alpha-D-myo-Phosphatidylinositol 4,5-bisphosphate[PI(4,5)P2]3-O-phospho linked, D(+)-sn-1,2-di-O-octanoylglyceryl,CellSignals #901) are mixed and incubated in the plate with compound for30 min prior to starting the reaction with the addition of P³³-ATP andMgCl₂ (reagents added using Zoom). Enzyme-free wells (column 18) aretypically done to determine the low control. PEI-PS Leadseeker beads inPBS/EDTA/CHAPS are added (by Multidrop) to quench the reaction, and theplates are allowed to incubate for at least one hour (typicallyovernight) before centrifugation. The signal is determined using aViewlux detector and is then imported into curve fitting software(Activity Base) for construction of concentration response curves. Thepercent inhibition of activity is calculated relative to high controls(C1, 0. 1 μl DMSO in column 6, rows A-P)) and low controls (C2, 5 μl of40 uM PIP2 in buffer in column 18, rows A-P) using,100*(1-(U1-C2)/(C1-C2)). The concentration of test compound yielding 50%inhibition is determined using the equation, y=((Vmax*x)/(K+x))+Y2,where “K” is equal to the IC50. The IC50 values are converted to pIC50values, i.e., −log IC50 in Molar concentration.

Celluar Assays:

Day 1

-   -   Plate cells before noon        -   10K cells/well in clear flat-bottomed 96-well plates (fv.            105 ul)        -   Last four wells in last column receive media only        -   Place in 37 degC incubator overnight        -   Compound plate        -   Prepare in polypropylene round-bottomed 96-well plates; 8            compounds per    -   plate, 11-pt titrations of each (3× serial dilution), DMSO in        last column (0.15% f.c. on cells)        -   15 ul in first well, 10 ul DMSO in the rest; take 5 ul from            first well and mix in next, continue across plate (excluding            last column); seal with foil lid and place at 4 degC.

Day 2

-   -   Take out Lysis buffer inhibitors (4-degC/−20 degC) and compound        plates (4 degC), thaw on bench top; make 1× Tris wash buffer        (WB) to fill reservoir on plate washer and top off bench supply        (use MiliQ), turn on centrifuge to allow it to cool    -   Block MSD plates        -   Make 20 ml 3% blocking solution/plate (600 mg blocker A in            20 ml WB), add 150 ul/well and incubate at RT for at least 1            hr    -   Add compound (while blocking)        -   Add 300 ul growth media (RPMI w/Q, 10% FBS) per well (682×            dil of compound) to each compound plate        -   Add 5 ul compound dilution into each well (f.v. 110 ul) on            duplicate plates        -   Place in 37 degC incubator for 30 min    -   Make lysates        -   Prepare MSD Lysis buffer; for 10 ml add 200 ul protease            inhibitor solution, and 100 ul each of Phosphatase            inhibitors I & II (Keep on ice until ready for use)        -   Remove plates post-incubation, aspirate media with plate            washer, wash 1× with cold PBS, and add 80 ul MSD Lysis            buffer per well; incubate on shaker at 4 degC for ≧30 min        -   Spin cold at 2500 rpm for 10 min; leave plates in 4 degC            centrifuge until ready for use    -   AKT duplex assay        -   Wash plates (4× with 200 ul/well WB in plate washer); tap            plates on paper towel to blot        -   Add 60 ul of lysates/well, incubate on shaker at RT for 1 hr        -   During incubation prepare detection Ab (3 ml/plate; 2 ml WB            and 1 ml blocking solution w/Ab at 10 nM); repeat wash step            as above        -   Add 25 ul of Ab/well, incubate on shaker at RT for 1 hr;            repeat wash step as above        -   Add 150 ul/well 1× Read Buffer (dilute 4× stock in ddH2O, 20            ml/plate), read immediately    -   Analysis        -   Observe all the data points at each compound concentration.        -   The data point from highest inhibitor concentration must be            equal or greater than 70% of DMSO control.        -   IC50 for duplicate runs must be within 2-fold of each other            (not flagged in summary template).        -   Y min must be greater than zero; if both mins are red            flagged (>35) then compound is listed as inactive            (IC50=>highest dose). If only one min is red flagged, but            still ≦50 then call IC50 as listed.        -   Any data points equal or greater than 30% off the curve will            not be considered.            Cell Growth/Death Assay:

BT474, HCC1954 and T-47D (human breast) were cultured in RPMI-1640containing 10% fetal bovine serum at 37° C. in 5% CO₂ incubator. Cellswere split into T75 flask (Falcon #353136) two to three days prior toassay set up at density which yields approximately 70-80% confluence attime of harvest for assay. Cells were harvested using 0.25% trypsin-EDTA(Sigma #4049). Cell counts were performed on cell suspension usingTrypan Blue exclusion staining. Cells were then plated in 384 well blackflat bottom polystyrene (Greiner #781086) in 48 μl of culture media perwell at 1,000 cells/well. All plates were placed at 5% CO₂, 37° C.overnight and test compounds were added the following day. One plate wastreated with CellTiter-Glo (Promega #G7573) for a day 0 (t=0)measurement and read as described below. The test compounds wereprepared in clear bottom polypropylene 384 well plates (Greiner#781280)with consecutive two fold dilutions. 4 μl of these dilutions were addedto 105 μl culture media, after mixing the solution, 2 μl of thesedilutions were added into each well of the cell plates. The finalconcentration of DMSO in all wells was 0.15%. Cells were incubated at37° C., 5% CO₂ for 72 hours. Following 72 hours of incubation withcompounds each plate was developed and read. CellTiter-Glo reagent wasadded to assay plates using a volume equivalent to the cell culturevolume in the wells. Plates were shaken for approximately two minutesand incubated at room temperature for approximately 30 minutes andchemiluminescent signal was read on the Analyst GT (Molecular Devices)reader. Results were expressed as a percent of the t=0 and plottedagainst the compound concentration. Cell growth inhibition wasdetermined for each compound by fitting the dose response with a 4 or 6parameter curve fit using XLfit software and determining theconcentration that inhibited 50% of the cell growth (gIC50) with the Ymin as the t=0 and Y max as the DMSO control. Value from wells with nocells was subtracted from all samples for background correction.

ADDITIONAL REFERENCES

The compounds of the present invention can also be tested to determinetheir inhibitory activity at PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ according tothe assays in the following references:

For all PI3K isoforms:

-   1. Cloning, expression, purification, and characterization of the    human Class Ia phosphoinositide 3-kinase isoforms: Meier, T. I.;    Cook, J. A.; Thomas, J. E.; Radding, J. A.; Horn, C.; Lingaraj, T.;    Smith, M. C. Protein Expr. Purif., 2004, 35(2), 218.-   2. Competitive fluorescence polarization assays for the detection of    phosphoinositide kinase and phosphatase activity: Drees, B. E.;    Weipert, A.; Hudson, H.; Ferguson, C. G.; Chakravarty, L.;    Prestwich, G. D. Comb. Chem. High Throughput Screen., 2003, 6(4),    321.    For PI3Kγ: WO 2005/011686 A1

The pharmaceutically active compounds within the scope of this inventionare useful as PI3 Kinase inhibitors in mammals, particularly humans, inneed thereof.

The present invention therefore provides a method of treating diseasesassociated with PI3 kinase inhibition, particularly: autoimmunedisorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, platelet aggregation, cancer, sperm motility,transplantation rejection, graft rejection and lung injuries and otherconditions requiring PI3 kinase modulation/inhibition, which comprisesadministering an effective compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. The compounds of Formula (I) also provide for amethod of treating the above indicated disease states because of theirability to act as PI3 inhibitors. The drug may be administered to apatient in need thereof by any conventional route of administration,including, but not limited to, intravenous, intramuscular, oral,subcutaneous, intradermal, and parenteral.

The pharmaceutically active compounds of the present invention areincorporated into convenient dosage forms such as capsules, tablets, orinjectable preparations. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include, starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid such as an ampoule, or anaqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desired oralor parenteral products.

Doses of the presently invented pharmaceutically active compounds in apharmaceutical dosage unit as described above will be an efficacious,nontoxic quantity preferably selected from the range of 0.001-100 mg/kgof active compound, preferably 0.001-50 mg/kg. When treating a humanpatient in need of a PI3K inhibitor, the selected dose is administeredpreferably from 1-6 times daily, orally or parenterally. Preferred formsof parenteral administration include topically, rectally, transdermally,by injection and continuously by infusion. Oral dosage units for humanadministration preferably contain from 0.05 to 3500 mg of activecompound. Oral administration, which uses lower dosages is preferred.Parenteral administration, at high dosages, however, also can be usedwhen safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular PI3 kinaseinhibitor in use, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Additionalfactors depending on the particular patient being treated will result ina need to adjust dosages, including patient age, weight, diet, and timeof administration.

The method of this invention of inducing PI3 kinase inhibitory activityin mammals, including humans, comprises administering to a subject inneed of such activity an effective PI3 kinase modulating/inhibitingamount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use as a PI3 kinase inhibitor.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) inthe manufacture of a medicament for use in treating autoimmunedisorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, platelet aggregation, cancer, sperm motility,transplantation rejection, graft rejection and lung injuries.

The invention also provides for a pharmaceutical composition for use asa PI3 inhibitor which comprises a compound of Formula (I) or apharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use inthe treatment of autoimmune disorders, inflammatory diseases,cardiovascular diseases, neurodegenerative diseases, allergy, asthma,pancreatitis, multiorgan failure, kidney diseases, platelet aggregation,cancer, sperm motility, transplantation rejection, graft rejection andlung injuries, which comprises a compound of Formula (I) or apharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the presentinvention can be co-administered with further active ingredients,including compounds known to have utility when used in combination witha PI3 kinase inhibitor.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent.

The following examples are, therefore, to be construed as merelyillustrative and not a limitation of the scope of the present inventionin any way.

Experimental Details

The compounds of the following examples are readily made according toSchemes 1 or by analogous methods.

Conditions: a) 2 M HCl in diethylether, THF, rt; then sodium iodide,propionitrile, reflux; b) aryl (R1) bromide, palladium catalyst, 2 MK₂CO₃, dioxane, heat; c) bis(pinacolato)diboron, potassium acetate,palladium catalyst, dioxane, heat; d) heteroaryl (R2) bromide, palladiumcatalyst, saturated aqueous NaHCO₃, dioxane, heat.

Example 1 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide

a) 6-bromo-4-iodoquinoline

Following the general procedure of Wolf, Christian et al. (SynLett 200312, 1801-1804), to a solution of 6-bromo-4-chloroquinoline (30 g, 0.124mol) in anhydrous THF (500 mL) was added 2 M HCl in diethylether (74 mL,0.148 mol). A white precipitate formed immediately. After stirring for30 min, the suspension was concentrated in vacuo and dried under vacuumto provide 6-bromo-4-chloroquinoline hydrochloride as an off-white solid(34.6 g, quantitative yield).

A 3-neck roundbottom flask equipped with a reflux condenser andmechanical stirrer was charged with 6-bromo-4-chloroquinolinehydrochloride (34.6 g, 0.124 mol), anhydrous sodium iodide (92.93 g,0.62 mol) and propionitrile (1 L). The resulting slurry was stirredvigorously at reflux for 96 hrs. The solution was cooled to roomtemperature and 500 mL of 10% K₂CO₃ solution was added, followed by a200 mL of a 5% sodium sulfite solution. The reaction mixture wasextracted with CH₂Cl₂ (600 mL×4). The combined organic extracts weredried (Na₂SO₄), filtered and conc. in vacuo to provide the titlecompound as an off-white solid (41.8 g, >quantitative yield), which wasused without further purification. LCMS [α]⁺=333.8, 334.8, 336.0 and337.0; H¹ NMR (400 MHz, d-DMSO) δ (ppm)=7.98-7.96 (2H, m), 8.14-8.16(1H, m), 8.23 (1H, d), 8.53 (1H, d).

b) 6-bromo-4-(4-pyridinyl)quinoline

A 1 L sealed tube charged with 6-bromo-4-iodoquinoline (11.58 g, 0.0347mol), 4-pyridineboronic acid (5.97 g, 0.0486 mol),tetrakis(triphenyphosphine)palladium[0] (2.0 g, 0.00173 mol), 2 Maqueous potassium carbonate (152 mL) and 1,4-dioxane (152 mL) wasstirred at 100° C. for 28 hrs. After cooling to rt, the organic layerwas separated and the aqueous portion extracted with EtOAc (200 mL×3).The combined organic extracts were dried (Na₂SO₄), filtered andpartially concentrated in vacuo. The resultant mixture was filtered togive the title compound (9.13 g) as a tan solid. The residualsupernatant was concentrated to dryness and purified by silica gelchromatography (100% ethyl acetate to 2% methanol in ethyl acetate) toprovide an additional 0.036 g of the title compound as a tan solid(combined 9.166 g, 92% yield).

LCMS [α]⁺=285.9; 287.8. H¹ NMR (400 MHz, d-DMSO) δ (ppm)=7.53-7.71 (3H,m), 7.85 (1H, s), 8.05 (1H, d), 8.17 (1H, d), 8.81 (2H, d), 9.05 (1H, d)

c)4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

A mixture of (6-bromo-4-(4-pyridinyl)quinoline (5.0 g, 17.5 mmol),bis(pinacolato)diboron (4.9 g, 19.3 mmole), potassium acetate (5.2 g,52.6 mmol), and dichloro-[1,1′bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (430 mg, 0.53 mmol) in dioxane (30 mL) washeated at 130° C. for 4 h and cooled to room temperature. The reactionwas cooled and filtered through Na₂SO₄ and Celite onto silica. Themixture was purified by silica gel chromatography eluting withEtOAc/ethanol (0-20% methanol gradient) to give the title compound as asemi-pure solid. (2.14 g, 64%) mix of boronic acid and ester usedwithout further purification.

d) 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide

A mixture of4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(250 mg, 0.75 mmol), 5-bromopyridine-3-sulfonamide (213 mg, 0.9 mmol),tetrakistriphenylphosphine palladium (0) (95 mg, 0.08 mmol), andsaturated aqueous NaHCO₃ (2.5 mL), and dioxane (5 mL)) was heated at120° C. for 1 h and cooled to room temperature. The reaction mixture wasfiltered through Celite and the solvent was removed under reducedpressure. The crude product was purified by Gilson reverse phase HPLC(8-25% 6 min gradient 0.1% TFA in H₂O/CH₃CN) followed by neutralizationwith saturated aqueous NaHCO₃ and extracted into EtOAc. Evaporationprovided the title compound as an off white solid. (85 mg, 31%). ESMS[M+H]⁺=363.1

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 1:

MS(ES) Example Structure [M + H]⁺ 2

338 3

411 4

448 5

392 6

406 7

378 8

367 9

338 10

338 11

436 12

447 13

525 14

489 15

444 16

461 17

491 18

490 19

503 20

454 21

454 22

557 23

436 24

476 25

462 26

476 27

504 28

477 29

463 30

396 31

340 32

341 33

324 34

324 35

300 36

323 37

339 38

339 39

409 40

417 41

411 42

324 43

340 44

337 45

355 46

339 47

352 48

284 49

325 50

341 51

351 52

420 53

420 59

475 60

324 61

407 62

395 63

395 64

498 65

485 66

364 67

352 68

366 69

300 70

313 71

433 72

341 73

363 74

341 75

352 76

377 77

391 78

328 79

355 80

352 81

469 82

475 83

362 84

468 85

422 86

462 87

421 88

436 89

418 90

498 91

419 92

447 93

417 94

407 95

453 96

460 97

446 98

403 99

421 100

439 101

483 102

453 103

440 104

473.2 105

445.3 106

469.1 249

489.1 250

453.0 251

532 252

487.1 253

478.9 254

505.1 255

492.1 256

411.1 257

426 258

441 259

396 260

492 261

535 262

525 263

521 264

492 265

490 266

487 267

507 268

453 269

442 270

464 271

391 272

468 273

481 274

484 275

478 276

418 277

491 278

437

Conditions: a) heteroaryl (R2) boronic acid or heteroaryl (R2) boronate,palladium catalyst, 2 M potassium carbonate, heat; or heteroaryl (R2)stannane, palladium catalyst, dioxane, heat.

Example 107 6-[5-(methylsulfonyl)-3-pyridinyl]-4-(4-pyridinyl)quinoline

A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol),5-methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol),tetrakistriphenylphosphine palladium (0) (104 mg, 0.09 mmol), and sat.aqueous NaHCO₃ (1.75 mL), in dioxane (5 mL) was heated at 110° C. for 1h then cooled to room temperature. The r×n was filtered through Celiteand Na₂SO₄ onto silica and the crude product was purified by columnchromatography (5% EtOAc/Hex—10% Ethanol/EtOAc; 30 min gradient).Evaporation and precipitation from MeOH/water (2/98) provided the titlecompound as a yellow solid. (160 mg, 50%). ESMS [M+H]⁺=362.1

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 107:

MS(ES) Example Structure [M + H]⁺ 108

323 109

284 110

284 111

285 112

527 113

391 114

313 115

313 116

314 117

317 118

285 119

301 120

344 121

382 122

369 123

318 124

328 125

385 126

412 127

368 128

313 129

302 130

310 131

313 132

309 133

313 134

397 135

3130 136

317 137

298 138

330 139

362 279

334.1

Conditions: a) aryl (R1) boronic acid or aryl (R1) boronate, palladiumcatalyst, 2 M potassium carbonate, dioxane, heat; then heteroaryl (R2)boronic acid or heteroaryl (R2) boronate, palladium catalyst, 2 Mpotassium carbonate, heat.

Example 1392-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide

A mixture of 4-iodo-6-bromoquinoline (1.18 g, 3.53 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (1 g,3.53 mmol), dichloro-[1,1′bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (177 mg, 0.176 mmol), 2 M potassiumcarbonate (5 mL), in dioxane (15 mL) was heated at 100° C. for 1.5 h andcooled to room temperature. LCMS indicated the reaction was finished. Tothe finished reaction was added2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide(1.2 g, 4 mmol), Dichloro-[1,1′bis(diphenylphosphino)ferrocene]Palladium (II) dichloromethane adduct (177 mg, 0.176 mmol),and 2 M potassium carbonate (5 mL). The reaction was heated at 100° C.for 3 h and cooled to room temperature. The dioxane and water wereseparated and the dioxane evaporated to get the crude product which waspurified on silica gel eluting with ethyl acetate/methanol, 0-3%methanol. The product which crystallized from ethyl acetate containedethyl acetate. The ethyl acetate was removed by dissolving the productin a excess of acetone and evaporation. Residual acetone was thenremoved by triturating with distilled water at 60 deg followed byfiltration and drying under vacuum. A yield of the title compound (540mg, 31%) was obtained. MS(ES)+ m/e 484 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 139

Ex- MS(ES) am- [M + ple Structure H]⁺ 140

442 141

527 142

498 143

504 144

387 145

377 146

461 147

391 148

461 149

475 150

442 151

341 152

341

Conditions: a) aryl (R1) boronic acid or aryl (R1) boronate, palladiumcatalyst, 2 M potassium carbonate, dioxane, heat; b)bis(pinacolato)diboron, potassium acetate, palladium catalyst, dioxane,heat; then heteroaryl (R2) bromide, palladium catalyst, 2 M potassiumcarbonate, heat.

Example 1532-amino-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide

a) 6-bromo-4-(1H-pyrazol-4-yl)quinoline

A mixture of 6-bromo-4-iodoquinoline (1.37 g, 4 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (852 mg, 4mmol), dichloro-[1,1′bis(diphenylphosphino) ferrocene]palladium (II)dichloromethane adduct (162 mg, 0.2 mmol), 2 M potassium carbonate (6mL), in dioxane (25 mL) was heated at 100° C. for 1.5 h and cooled toroom temperature. The dioxane and water were separated and the dioxaneevaporated to get the crude product which was purified on silica geleluting with ethyl acetate/methanol, 0-3% methanol. A yield of the titlecompound (340 mg, 34%) was obtained. MS(ES)+ m/e 275 [M+H]⁺.

b) 2-amino-5-[4-(1H-pyrazol-4-yl)-6-quinolinyl]-3-pyridinesulfonamide

6-bromo-4-(1H-pyrazol-4-yl)quinoline (330 mg, 1.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (304 mg, 1.2mmol), dichloro-[1,1′bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (48 mg, 0.06 mmol), potassium acetate (352 mg,3.6 mmol), in dioxane (5 mL) was heated at 100° C. for 1.5 h and cooledto room temperature. LCMS indicated the reaction was complete (formationof4-(1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline).

To this same reaction mixture was addeddichloro-[1,1′bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (48 mg, 0.06 mmol),2-amino-5-bromo-3-pyridinesulfonamide (280 mg, 1 mmol) and 2 M potassiumcarbonate (1.5 mL). The reaction mixture was heated a second time to115° C. for 18 h. The dioxane and water were separated and the dioxaneevaporated. The crude product was trituated with methylene chloride(insoluble), then dissolved in DMF and filtered through a glass fiberfilter. The DMF was evaporated and the product triturated with methanol,filtered and dried. A yield of the title compound (108 mg, 22%, twosteps) was obtained. MS(ES)+ m/e 395 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 153

MS(ES) Example Structure [M + H]⁺ 154

401 155

352 156

323 157

338 158

323 159

323 160

338 161

402 162

322 163

322 164

338 165

338 166

351 167

351 168

388 169

351 170

324 171

368 172

342 173

299 174

383 175

381 176

366 177

434 178

352 179

353 180

327 181

357 182

314 183

341 184

352 185

352 186

350 187

439 188

473 280

411 281

407.2 282

349.7 283

416.9 284

332.7 285

469.1 286

417.3 287

453.0 288

475.1 289

460.2 290

432.2 291

435.2 292

509.1 293

513

Conditions: a) bis(pinacolato)diboron, p palladium catalyst, potassiumacetate, dioxane, heat; then heteroaryl (R2) bromide, palladiumcatalyst, 2 M potassium carbonate, heat; then aryl (R1) boronic acid oraryl (R1) boronate, palladium catalyst, 2 M potassium carbonate, heat.

Example 1892-amino-5-{4-[3-(aminosulfonyl)phenyl]-6-quinolinyl}-3-pyridinesulfonamide

This compound was prepared in one pot (three steps) with no workupsbetween steps. A mixture of 6-bromo-4-chloroquinoline, (484 mg, 2 mmol),bis(pinacolato)diboron, (506 mg, 2 mmol),dichloro-[1,1′bis(diphenylphosphino) ferrocene]palladium (II)dichloromethane adduct (81.5 mg, 0.1 mmol), and potassium acetate (588mg, 6 mmol) in dioxane (6 mL) was heated at 100° C. for 4 h. To thisreaction was added 2-amino-5-bromo-3-pyridinesulfonamide, (560 mg 2mmol) an equal amount of the palladium catalyst used above (0.1 mmol)and 2 M potassium carbonate (3 mL). The reaction was heated at 95 degcentigrade for one hour. To this reaction was added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, (566mg 2 mmol), dichloro-[1,1′bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (81.5 mg, 0.1 mmol) and 2 M potassiumcarbonate (3 mL). The reaction was heated at 95° C. for three hours. Thesolvent was evaporated and the crude material purified by silica gelchromatography, eluting with ethyl acetate. The product was purifiedfurther by crystallizing from hot ethyl acetate. Obtained 181 mg (18.7%)for three steps. MS(ES)+ m/e 484 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 189:

MS(ES) Ex- [M + ample Structure H]⁺ 190

420 191

484 192

420 193

572 194

405 195

420 196

469 294

514 295

489 296

514 297

492 298

514 299

492 300

542 301

552 302

492 303

542 304

581 305

581 306

517 307

517 308

531 309

531 310

311

Conditions: a) hexamethylditin, tetrakis(thriphenylphosphine)palladium(0), lithium chloride, tetrahydrofuran, heat; b) heteroaryl (R2)bromide, palladium catalyst, dioxane, heat.

Example 1974-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline

a) 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline

A mixture of 4-(4-pyridinyl)-6-bromoquinoline (15 g, 53 mmol),hexamethylditin (19 g, 59 mmol), lithium chloride (16 g, 370 mmol),tetrakis(triphenyphosphine)-palladium (0) (3 g, 2.7 mmol), intetrahydrofuran (400 mL) was heated at reflux for 16 hours, at whichtime the reaction was allowed to cool to room temperature andconcentrated under reduced pressure. Methylene chloride (500 mL) wasadded to the residue and the mixture was stirred for 2 hours to helpbreak up the solids. The mixture was then filtered and concentratedunder reduced pressure. The resulting residue was purified by silica gelchromatography (gradient: CH₂Cl₂ to 2% MeOH/CH₂Cl₂) to give the titlecompound (11 g, 56%) as a beige solid. MS(ES)+ m/e 370 [M+H]⁺.

b) 4-(4-pyridinyl)-6-(1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)quinoline

A mixture of 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.5mmol), 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline (204 mg, 0.55mmol), and tetrakistriphenylphosphine palladium(0) (29 mg, 0.025 mmol)in 1,4-dioxane (3.0 mL) was heated at 100° C. for 18 h. The reaction wasfiltered to collect the precipitate. The solid was triturated in hotethanol to give an off-white solid, which still contained some minorimpurities. The off-white solid was triturated in hot ethanol to givethe title product as a beige solid (22 mg, 14%). MS(ES)+ m/e 325.1[M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 197:

MS(ES) Example Structure [M + H]⁺ 198

324 199

325 200

323 201

324 202

379 203

381

Conditions: a) diethylethoxymethylene malonate, 140° C., then DowthermA, 260° C.; b) 6 N sodium hydroxide, ethanol, reflux; c) Dowtherm A,260° C.; d) phosphorous oxychloride, reflux; e) bis(pinacolato)diboron,palladium catalyst, potassium acetate, dioxane, heat; then heteroaryl(R2) bromide, palladium catalyst, 2 M aqueous potassium carbonate, heat;then aryl (R1) boronic acid/ester, palladium catalyst, 2 M aqueouspotassium carbonate, dioxane, heat.

Example 2042-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide

a) ethyl 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate

A mixture of 4-bromo-2-methylaniline (1.50 g, 8.04 mmol) anddiethylethoxymethylene malonate (1.74 g, 8.04 mmol) was heated at 140°C. with stirring in an oil bath for 5.0 h. The reaction was transferredto a heating mantle, diluted with Dowtherm A (4 mL), and heated at 260°C. for 1 h. The reaction was cooled, diluted with hexanes, and thesuspension was stirred overnight at room temperature. The suspension wasfiltered and the filtered solid was washed with hexanes and dried in aBuchner funnel to give the title compound (1.90 g, 76%) as a tan solid.MS(ES)+ m/e 310 [M+H].

b) 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid

A mixture of ethyl 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate(1.89 g, 6.09 mmol) and 6 N NaOH (1.22 g, 30.45 mmol, 5.1 mL) in ethanol(30 mL) was heated at reflux for 2.0 h and concentrated in vacuo. Theresidue was diluted with water and acidified with 6 N HCl to pH 4. Theresulting solid was filtered, washed with water and diethyl ether, anddried overnight in a Buchner funnel to give the title compound (1.72 g,99%) as a tan solid. MS(ES)+ m/e 282 [M+H].

c) 6-bromo-8-methyl-4-quinolinol

A mixture of 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylic acid (1.80g, 6.36 mmol) and Dowtherm A (10 mL) was heated at 260° C. for 1.0 h.The reaction was cooled, triturated with hexanes, filtered and dried ina Buchner funnel to give the title compound (1.43 g, 95%) as a tansolid. MS(ES)+ m/e 238 [M+H].

d) 6-bromo-4-chloro-8-methylquinoline

A mixture of 6-bromo-8-methyl-4-quinolinol (1.42 g, 5.95 mmol) andphosphorous oxychloride (10.95 g, 71.40 mmol) was heated at reflux for 1h, cooled, poured onto ice, and neutralized by addition of 30% ammoniumhydroxide. The resulting solid was filtered and dried in a vacuum ovento give the title compound (1.45 g, 95%) as a tan solid. MS(ES)+ m/e 256[M+H].

e)2-amino-N,N-dimethyl-5-[8-methyl-4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonamide

A mixture of 6-bromo-4-chloro-8-methylquinoline (0.300 g, 1.170 mmol),bis(pinacolato)diboron (0.297 g, 1.170 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.029 g, 0.035 mmol), and solid anhydrouspotassium acetate (0.459 g, 4.676 mmol) in dry 1,4-dioxane (8 mL) washeated at reflux for 70 minutes. The oil bath was temporarily removedand to the reaction was added2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide (0.327 g, 1.17 mmol),dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.047 g, 0.058 mmol), and 2 M aqueous potassiumcarbonate (0.646 g, 4.676 mmol, 2.34 mL). The reaction was heated atreflux for 80 minutes. The oil bath was temporarily removed and to thereaction was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.240 g, 1.17mmol), dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.047 g, 0.058 mmol), 2 M aqueous potassiumcarbonate (0.485 g, 3.51 mmol, 1.76 mL), and 1,4-dioxane (6 mL). Thereaction was heated at reflux for 17 h and concentrated in vacuo. Theresidue was triturated with 10% MeOH:EtOAc (45 mL), filtered throughfilter paper, and the filtrate was concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (7% MeOH:EtOAc) togive the title compound (0.135 g, 28%) as a yellow powder. MS(ES)+ m/e420 [M+H].

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 204:

MS(ES) Example Structure [M + H]⁺ 205

424 206

420 207

424 208

381 209

377 210

377

Conditions: a) bis(pinacolato)diboron, potassium acetate, palladiumcatalyst, dioxane, heat; then 5-bromo-2-pyridinamine, palladiumcatalyst, 2 M potassium carbonate, dioxane, heat; b) chlorosulfonicacid, 0° C.—reflux; c) R₆R₇NH, pyridine, dioxane, rt-50° C.

Example 2113-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine

a) 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine

To a 1 L pressure vessel was added 6-bromo-4-(4-pyridinyl)quinoline (12g, 42.08 mmol), bis(pinacolato)diboron (12.8 g, 50.5 mmol), anhydrouspotassium acetate (8.24 g, 84.16 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complexwith dichloromethane(1:1) (1.372 g, 1.68 mmol) and anhydrous dioxane(420 mL). The reaction vessel was purged with nitrogen, capped andheated at 100° C. for 15 hours. LCMS indicated 96% conversion to amixture of the desired boronate ester MS(ES)+ m/e 333.2 [M+H]⁺ andboronic acid MS(ES)+m/e 250.9 [M+H]⁺.

To the reaction mixture above was added 5-bromo-2-pyridinamine (7.28 g,42.08 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complexwith dichloromethane(1:1) (1.718 g, 2.1 mmol), 2 M aqueous K₂CO₃ (300mL). The reaction was heated at 100° C. for 21 hours. After cooling toroom temperature, the organic layer was separated and concentrated invacuo. The residue was triturated with water, and dissolved indichloromethane. This solution was filtered through a plug of silica,washing continuously with dicholormethane and ethanol. Concentration invacuo provided the title compound as a yellow powder (8.767 g, 70%yield). MS(ES)+ m/e 299.0 [M+H]⁺.

b) 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl chloride

To cold (0° C.) chlorosulfonic acid (15 mL) under vigorous stirring wasadded 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine (4.348 g, 14.57mmol) portionwise. The reaction mixture was then heated at reflux for 16hrs. Upon cooling to room temperature, LCMS indicated 47% of the titlecompound MS(ES)+m/e 396.9 [M+]⁺ and 37% of sulfonic acid by-productMS(ES)+ m/e 379.1 [M+]⁺. A 2 mL aliquot of this 0.456M solution of thetitle compound was used in the next reaction without further workup.

c)3-(1-piperidinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine

To a cold (5° C.) solution of the 0.456 M solution of2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl chloride (2mL, 0.912 mmol) in chlorosulfonic acid from above was added anhydrousdioxane (1 mL) and piperidine (1.8 mL, 18.24 mmol). After 30 minutes ofstirring, pyridine (1 mL, 12.3 mmol) was added and the reaction mixturestirred for an additional hour at room temperature. The reaction mixturewas concentrated in vacuo, the residue dissolved in CH₂Cl₂ and the pHadjusted to 14 using 6 N NaOH (aq). The solution was extracted withCH₂Cl₂ (×4) and the combined organic layers dried (Na₂SO₄), filtered andconcentrated in vacuo. The resulting residue was purified twice bysilica gel chromatography (0-5% MeOH in EtOAC) to give the titlecompound as a pale yellow solid (269 mg, 66% yield). MS(ES)+ m/e 446.3[M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 211:

MS Ex- (ES) am- [M + ple Structure H]⁺ 212

446 213

406 214

463 215

469 216

454 217

453 218

434 219

432

Conditions: a) aryl (R1) boronic acid or aryl (R1) boronate, palladiumcatalyst, 2 M potassium carbonate, dioxane, heat; b)bis(pinacolato)diboron, potassium acetate, palladium catalyst, dioxane,heat; then heteroaryl (R2) bromide, palladium catalyst, 2 M potassiumcarbonate, heat.

Example 220 Preparation of6-(1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline

a) 4-(4-pyridinyl)-6-quinolinecarbonitrile

A mixture of 4-chloro-6-quinolinecarbonitrile (8.7 g, 46.2 mmol),4-pyridineboronic acid (8.52 g, 69.3 mmol),tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and 2 Mpotassium carbonate (69.3 mL, 3 eq) in 1,4-dioxane (380 mL) is heated atreflux for 3.5 hours. The dioxane is evaporated and the crude productpurified by silica gel chromatography eluting with methylenechloride/methanol 0-4%. A yield of 10.23 g (95%) of the title compoundswas obtained.

b) 1H-benzimidazol-2-yl)-4-(4-pyridinyl)quinoline

A mixture of 4-(4-pyridinyl)-6-quinolinecarbonitrile, (231 mg, 1 mmol)1,2-diaminobenzene (108 mg, 1 mmol) and polyphosphoric acid (1.4 g) washeated in the microwave at 250° C. for 1.5 hours. The reaction waspoured onto water which was neutralized with bicarbonate. The productwas filtered, washed with water, and dried. The product was furtherpurified by dissolving in hot methanol, filtering and cooling to obtaincrystals. The yield was 47.7 mg, 30%. MS(ES)+M/e 323 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 220:

MS(ES) Example Structure [M + H]⁺ 221

323 222

324 223

324 224

325

Conditions: a) cyclic secondary amine, dimethylformamide, heat; b)bis(pinacolato)diboron, potassium acetate, palladium catalyst, dioxane,heat; then heteroaryl (R2) bromide, palladium catalyst, 2 M potassiumcarbonate, heat.

Example 2254-(1-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

a) 6-bromo-4-(1-piperidinyl)quinoline

To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL of1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol). Thereaction was heated to 150° C. for 5 h. The solvents were removed invacuo at 100° C. and the residue dissolved in methylene chloride andwashed with water. The methylene chloride was dried with sodium sulfateand concentrated. The residue was triturated with hexane and the solidfiltered off to give 6-bromo-4-(1-piperidinyl) quinoline (877 mg, 73%).

b)6-(7,7a-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(1-piperidinyl)quinoline

To a solution of 6-bromo-4-(1-piperidinyl)quinoline (429 mg, 1.47 mmol)in dioxane (4 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (373 mg, 1.76mmol), potassium acetate (441 mg, 4.5 mmol), and PdCl2(dppf)₂ (36 mg,0.045 mmol). The reaction was heated to 150° C. for 30 minutes to givecrude4-(1-piperidinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline.The reaction was then cooled and5-bromo-7,7a-dihydro-1H-pyrazolo[3,4-b]pyridine (348 mg, 1.76 mmol) wasadded, followed by PdCl2(dppf)₂ (36 mg, 0.045 mmol) and 2 M potassiumcarbonate (2.25 mL). The reaction was heated at 150° C. for 30 min, atwhich time the dioxane was evaporated and the crude product trituratedwater and collected by filtration. The crude product was partiallypurified by HPLC chromatography acetonitrile/water/0.1% TFA. At thispoint the product was 85% pure. It was free based with sodium carbonateand further purified by silica gel chromatography eluting with methylenechloride/0-2% (methanol/concentrated ammonium hydroxide solution 9/1) toobtain the title compound (29 mg, 0 6%). MS(ES)+ m/e 330 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 225:

MS(ES) Example Structure [M + H]⁺ 226

332 227

345 228

330 229

332

Conditions: a) R-sulfonyl chloride, pyridine, methylene chloride.

Example 2302,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide

a)2,4-difluoro-N-{5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide

A solution of 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine (82 mg,0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat2,4-difluorobenzenesulfonyl chloride in one portion. The reaction wasstirred at room temperature for 30 minutes then was purified directly byprep-HPLC. The combined, desired fractions were evaporated under reducedpressure to remove organic solvents then diluted with small portions ofbrine and saturated aqueous sodium bicarbonate. The basic solution wasextracted with ethyl acetate then the extracts were dried over anhydroussodium sulfate and evaporated under reduced pressure. The resultingcolorless film was crystallized from methylene chloride and diethylether. The solids were collected by filtration, rinsed with diethylether then vacuum dried to afford the title compound (219 mg, 48%) as awhite solid. MS(ES)+ m/e 475 [M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 230:

MS(ES) Example Structure [M + H]⁺ 231

443 232

445 233

458 234

499 235

419 236

403 237

439 238

453 312

457 313

457 314

469 315

457 316

484 317

464 318

507 319

507 320

440.1 321

457.1 322

511.1 323

471.2 324

483.1 325

406.3 326

418.3 327

443.2 328

498.2 329

429 330

453 331

471.2 332

500.3 333

547.0, 549.1 334

512.2 335

498.2 336

457.1 337

525.4 338

471.2 339

429.1 340

457.1 341

507 342

507 343

581.9 344

432.2Some non-commercially available heteroaryl (R1) bromides were preparedand coupled to the corresponding boronic ester or boronic acid as notedabove.

Conditions: a) Chlorosulfonic acid, 0° C.—reflux; b) Morpholine,pyridine, dioxane, 5° C.—rt—50° C.

Example 2393-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine

a) 2-amino-5-bromo-3-pyridinesulfonyl chloride

To a cooled (0° C.) solution of chlorosulfonic acid (58 mL) undervigorous stirring was added 5-bromo-2-pyridinamine (15 g, 86.7 mmol)portionwise. The reaction mixture was then heated at reflux for 3 hrs.Upon cooling to room temperature, the reaction mixture was poured overice (p100 g) with vigorous stirring. The resulting yellow precipitatewas collected by suction filtration, washing with cold water andpetroleum ether to provide the title compound as an orange-yellow solid(18.1 g, 77% yield). MS(ES)+ m/e 272.8 [M+H]⁺.

b) 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine

To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50 g,1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5° C. was added (0.16mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) ofpyridine. The reaction mixture was stirred at room temperature for 2 hrsand then heated at 50° C. for 1 hour. After cooling to room temperature,a white precipitate formed which was collected by suction filtration,washing with water and petroleum ether to give the title compound as anoff-white solid. (0.539 g, 91% yield). MS(ES)+ m/e 323.9 [M+H]⁺.

c)3-(4-morpholinylsulfonyl)-5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine

A mixture of 5-bromo-3-(4-morpholinylsulfonyl)-2-pyridinamine (0.296 g,0.92 mmol),4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(0.306 mg, 0.92 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-complexwith dichloromethane(1:1) (37.6 mg, 0.046 mmol), 2 M aqueous K₂CO₃ (5mL) and dioxane (5 mL) was heated at 100° C. for 18 h. After cooling toroom temperature, the organic layer was separated and the aqueousportion extracted three times with EtOAc. The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified twice by silica gel chromatography (eluent: i) 1-5% MeOH inCH₂Cl₂ and ii) 0-20% MeOH in CH₂Cl₂) to provide the title compound as awhite solid (150 mg, 37% yield). MS(ES)+ m/e 448.0 [M+H]⁺.

Conditions: a) i) LDA, THF, −78° C.; ii) N-formylpiperidine, −78° C.; b)i) pinacol, p-TsOH, benzene, reflux; ii) anhydrous hydrazine, DIPEA,EtOH, reflux; c) conc aq HCl (36.5%-38%), EtOH, H₂O, 60° C. to rt.

Example 240 5-bromo-1H-pyrazolo[3,4-b]pyridine

a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde

Following the procedure described in WO2006015124 and trituration of thecrude product in hexanes instead of crystallization from cyclohexaneafforded the title compound as an off-white solid (68%). MS(ES)+ m/e203.8, 205.7 [M+H]⁺.

b) 5-bromo-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2(1H)-pyridinonehydrazone

Following the procedure described in WO2006015124 without the additionof hydrogen chloride provided the title compound as a yellow solid.MS(ES)+ m/e 317.9 [M+H]⁺. This crude material was used directly in thenext step.

c) 5-bromo-1H-pyrazolo[3,4-b]pyridine

Following the procedure described in WO2006015124 provided the titlecompound as a yellow solid (94%, 2 steps). MS(ES)+ m/e 197.7, 199.7[M+H]⁺.

Conditions: a) tin(II) chloride, concentrated HCl, room temperature; b)R-sulfonyl chloride, pyridine, methylene chloride.

Example 241 N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide

a) 3-amino-5-bromo-2-chloropyridine

To a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (20.0 g,84.2 mMol) in conc. HCl (90 mL) was added SnCl₂.2H₂O (60.0 g, 266 mMol)portionwise over 2 h. (The reaction got very warm to the touch.) Thereaction was stirred at RT for 18 h, poured onto ice, and basified withaq. 6 N NaOH (300 mL). The resultant slurry was filtered, washed withH₂O, and dried under vacuum to give the title compound (15.53 g, 89%) asan off-white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.66 (d, J=2.3 Hz,1H), 7.30 (d, J=2.3 Hz, 1H), 5.90 (br. s., 2H); MS(ES) m/e 206.7 (M+H)⁺.

b) N-(5-bromo-2-chloro-3-pyridinyl)benzenesulfonamide

To a stirred solution of 3-amino-5-bromo-2-chloropyridine (5.0 g, 24mMol) in CH₂Cl₂ (50 mL) was added pyridine (3.0 mL, 37 mMol) followed bybenzenesulfonyl chloride (4.5 mL, 35 mMol) drop wise over 5 minutes. Thereaction was stirred at RT for 18 h and evaporated to dryness undervacuum. Purified by flash chromatography on silica gel (15% hexanes inCH₂Cl₂ then 0 to 5% EtOAc in 15% hexanes in CH₂Cl₂). During evaporationof the solvents the product crashed out. The resultant slurry wasdiluted with hexane, filtered and dried under vacuum to give the titlecompound (2.89 g, 34%) as a white solid. [An overlap fraction whichcontained 30% starting amine (2.60 g) was also obtained.]: ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.61 (br. s., 1H), 8.41 (d, J=2.27 Hz, 1H), 7.91(d, J=2.27 Hz, 1H), 7.73-7.77 (m, 2H), 7.67-7.72 (m, 1H), 7.56-7.64 (m,2H); MS(ES) m/e 346.7 (M+H)⁺.

Other non-commercially available heteroaryl (R1) bromides were preparedaccording to the following literature procedures and coupled to thecorresponding boronic ester as noted above:

WO2005110410 was used to prepare intermediates A-C.

Conditions: a) methyl (triphenylphosphoranylidene)acetate, methanol, rt;b) bromine, methylene chloride, rt; c) ii potassium hydroxide, ethanol,95° C.; ii] sulfuric acid, ethanol, 95° C.; d) potassium tert-butoxide,(R8)-hydrazine, tetrahydrofuran, rt—65° C.

Example 2421-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one

a) methyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propenoate

A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (2.29 g, 9.78mmol), methyl (triphenylphosphoranylidene)acetate (3.30 g, 9.78 mmol) inMeOH (75 mL) was stirred at room temperature for 1 hour. The reactionwas evaporated under reduced pressure and the resulting residue waspurified by silica gel chromatography (1% MeOH in EtOAc) to give thetitle compound (2.71 g, 95%) as a white solid. MS(ES)+ m/e 291 [M+H]⁺.

b) methyl 2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate

A solution of methyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propenoate (2.71g, 9.33 mmol) in dichloromethane (90 ml) was treated with neat bromine(4.80 ml, 9.33 mmol) then stirred at room temperature for 4 hours.Evaporation under reduced pressure gave the title compound (4.20 g,100%) as a yellow solid. MS(ES)+ m/e 451 [M+H]⁺.

c) ethyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate

A slurry of methyl2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate (4.20 g, 9.33mmol) in ethanol (120 ml) was treated with solid potassium hydroxidepellets in one portion then heated at 95° C. for 2 hours. The reactionwas cooled to room temperature then evaporated under reduced pressure.The resulting residue was diluted with ethanol (90 ml) and concentratedH₂SO₄ (3 ml) then heated at 95° C. for 3.5 hours. Cooled to roomtemperature then concentrated under reduced pressure. The resulting wetresidue was taken into a minimum of water then made neutral with theaddition of saturated aqueous NaHCO₃ solution. This solution wasextracted with EtOAc and the extracts were dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The resultingresidue was purified by silica gel chromatography (EtOAc) to give thetitle compound (1.68 g, 60%) as a pale yellow solid. MS(ES)+ m/e 303[M+H]⁺.

d)1-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-one

A solution of phenylhydrazine (0.093 ml, 0.95 mmol) in anhydrous THF(4.0 ml) was treated with a 1M solution of potassium tert-butoxide inTHF (1.89 ml, 1.89 mmol). The resulting solution was added to a solutionof ethyl 3-[4-(4-pyridinyl)-6-quinolinyl]-2-propynoate (0.268 g, 0.95mmol) in THF (10 ml). The resulting brown solution was stirred at roomtemperature for 1 hour then at 65° C. for 1 hour. The resulting orangeslurry was cooled to room temperature then concentrated under reducedpressure. The resulting residue was taken into saturated aqueous NaHCO₃then extracted into methylene chloride and the extracts were dried oversodium sulfate then evaporated under reduced pressure. The resulting oilwas purified by HPLC (acetonitrile/water, 5-80% gradient). The productwas concentrated to a residue then recrystallized from ethanol to givethe title compound (0.020 g, 6%) as a white solid. MS(ES)+ m/e 365[M+H]⁺.

The following compounds were or can be prepared following the generalprocedures used to prepare the compound of Example 242:

MS(ES) Example Structure [M + H]⁺ 243

379 244

399 245

289 246

303

Following the procedure used to prepare Example 242,2-ethyl-6-[4-(4-pyridinyl)-6-quinolinyl]-4(1H)-pyrimidinone was or canbe prepared by substituting ethylamidine hydrochloride for hydrazine.MS(ES)+ m/e 329 [M+H]⁺.

MS(ES) Example Structure [M + H]⁺ 247

329

Following the procedure used to prepare Example 242,2-phenyl-5-[4-(4-pyridinyl)-6-quinolinyl]-1,2-dihydro-3H-pyrazol-3-onewas or can be prepared by substituting an alkynyl methyl ester for thealkynyl ethyl ester. MS(ES)+ m/e 365 [M+H]⁺.

MS(ES) Example Structure [M + H]⁺ 248

365

Conditions: a) aryl (R1) stannane, palladium catalyst, dioxane, heat; b)bis(pinacolato)diboron, potassium acetate, palladium catalyst, dioxane,heat; then heteroaryl (R2) bromide, palladium catalyst, saturatedaqueous Na₂CO₃, dioxane, heat.

Example 3452,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide

a) 6-bromo-4-(4-pyridazinyl)quinoline

Dissolved 6-bromo-4-iodoquinoline (17.43 g, 52.2 mmol),4-(tributylstannanyl)pyridazine (19.27 g, 52.2 mmol), andPdCl2(dppf)-CH2Cl2 (2.132 g, 2.61 mmol) in 1,4-dioxane (200 mL) andheated to 105° C. After 3 h, added more palladium catalyst and heatedfor 6 h. Concentrated and dissolved in methylene chloride/methanol.Purified by column chromatography (combiflash) with 2% MeOH/EtOAc to 5%MeOH/EtOAc to give the crude title compound. Trituration with EtOAcfurnished 6-bromo-4-(4-pyridazinyl)quinoline (5.8 g, 20.27 mmol, 38.8%yield). MS(ES)+ m/e 285.9, 287.9 [M+H]⁺.

b)2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide

A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 mmol),bis(pinacolato)diboron (4.69 g, 18.45 mmol), PdCl2(dppf)-CH2Cl2 (530 mg,0.649 mmol) and potassium acetate (3.29 g, 33.6 mmol) in anhydrous1,4-dioxane (120 ml) was heated at 100° C. for 3 h. The completedisappearance of the starting bromide was observed by LCMS. The reactionwas then treated withN-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide(6.68 g, 17.61 mmol) and another portion of PdCl2(dppf)-CH2Cl2 (550 mg,0.673 mmol), then heated at 110° C. for 16 h. The reaction was allowedto cool to room temperature, filtered, and concentrated. Purification ofthe residue by chromatography (Analogix; 5% MeOH/5% CH2Cl2/90% EtOAC)gave 6.5 g (76%) desired product. MS(ES)+ m/e 505.9 [M+H]⁺.

The following examples were or can be prepared following the generalprocedure used in Example 345

MS(ES) Example Structure [M + H]⁺ 346

474 347

476 348

510Intermediates:Intermediate 1

Conditions: a) Tributyl(vinyl)tin, Pd(PPh₃)₄, dioxane, reflux; b) OsO₄,NaIO₄, 2,6-lutidine, t-BuOH, dioxane, H₂O, rt; c) (4-pyridyl)boronicacid, Pd(PPh₃)₄, 2 M K₂CO₃, DMF, 100 □C.

4-(4-pyridinyl)-6-quinolinecarbaldehyde

a) 4-chloro-6-ethenylquinoline

A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med.Chem., 21, 268 (1978)), tributyl(vinyl)tin (8.95 g, 28.22 mmol), andtetrakistriphenylphosphine palladium (0) (0.62 g, 0.54 mmol) in1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature,and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (0-4% MeOH:CH₂Cl₂) to give the titlecompound (5.1 g) as a pale yellow solid. MS(ES)+m/e 190 [M+H]⁺. Thismaterial was used directly in the next step.

b) 4-chloro-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol),2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g,107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution intert-butanol, 0.538 mmol) in 1,4-dioxane:H₂O (350 mL of 3:1 mixture) wasstirred for 3.5 h at room temperature and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel (CH₂Cl₂) togive the title compound (4.26 g, 83% for 2 steps) as a pale yellowsolid. MS (ES)+ m/e 192 [M+H]⁺.

c) 4-(4-pyridinyl)-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol),4-pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphinepalladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K₂CO₃ (7.02 g, 50.76mmol, 25.4 mls of 2M solution) in DMF (100 mL) was heated at 100° C. for3.0 h and cooled to room temperature. The mixture was filtered throughCelite and the Celite was washed with EtOAc. The filtrate wastransferred to a separatory funnel, washed with water and saturatedNaCl, dried (Na₂SO₄), filtered and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (5% MeOH:CH₂Cl₂) togive the title compound (2.03 g, 51%) as a tan solid. MS(ES)+ m/e 235[M+H]⁺.

Intermediate 2

Preparation of 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide

a) 2-amino-5-bromo-3-pyridinesulfonyl chloride

To a cooled (0° C.) solution of chlorosulfonic acid (58 mL) undervigorous stirring was added 5-bromo-2-pyridinamine (86.7 mmol)portionwise. The reaction mixture was then heated at reflux for 3 hrs.Upon cooling to room temperature, the reaction mixture was poured overice (˜100 g) with vigorous stirring. The resulting yellow precipitatewas collected by suction filtration, washing with cold water andpetroleum ether to provide the title compound as an orange-yellow solid(18.1 g, 77% yield). MS(ES)+ m/e 272.8 [M+H]⁺.

*Other sulfonyl chlorides can be prepared using this procedure byvarying the choice of substituted aryl or heteroaryl.

b) 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide

To a cold (0 □C) suspension of 2-amino-5-bromo-3-pyridinesulfonylchloride (92.1 mmol) in dry 1,4-dioxane (92 mL) was added pyridine(101.3 mmol) followed by a 2M solution of dimethylamine in THF (101.3mmol). The reaction was allowed to warm to rt for 2 h, heated to 50 □Cfor 1 h, then cooled to rt. After standing for 2 h, the precipitate wascollected by filtration and rinsed with a minimal amount of cold water.Drying the precipitate to constant weight under high vacuum provided14.1 g (55%) of the title compound as a white solid. MS(ES)+ m/e 279.8,282.0 [M+H]⁺.

*Other sulfonamides were or can be prepared using this procedure byvarying the choice of sulfonyl chloride and amine.

Intermediate 3

Preparation of2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide

c) To a solution of 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide(7.14 mmol) in 1,4-dioxane (35 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (7.86 mmol),potassium acetate (28.56 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)dichloromethane complex (1:1) (0.571 mmol). The reaction mixture wasstirred at 100° C. for 18 h. The reaction was concentrated in vacuo,re-dissolved in ethyl acetate (50 mL) and purified on silica using 60%ethyl acetate/hexanes to yield the title compound as a tan solid (86%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.41 (d, 1H, J=1.52), 7.92 (d, 1H,J=1.77), 2.68 (s, 6H), 1.28 (s, 12H).

*Other boronate or boronic acids can be prepared using this procedure byvarying the choice of aryl or heteroaryl bromide.

Conditions: a) NaO(R1), (R1)OH, 0° C. to room temperature; b)SnCl₂.2H₂O, ethyl acetate, reflux; c) (R2)SO₂Cl, pyridine, 0° C. to roomtemperature.Intermediate 4

Preparation ofN-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

a) 5-bromo-2-(methyloxy)-3-nitropyridine

To a cooled (0° C.) solution of 5-bromo-2-chloro-3-nitropyridine (50 g,211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20%sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quicklybecame heterogeneous, was allowed to warm to ambient temperature andstirred for 16 h. The reaction was filtered and the precipitate dilutedwith water (200 mL) and stirred for 1 h. The solids were filtered,washed with water (3×100 mL) and dried in a vac oven (40° C.) to give5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4% yield) as apale yellow powder. The original filtrate was concentrated in vacuo anddiluted with water (150 mL). Saturated ammonium chloride (25 mL) wasadded and the mixture stirred for 1 h. The solids were filtered, washedwith water, and dried in a vac oven (40° C.) to give a second crop of5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34% yield).Total yield=90%. MS(ES)+ m/e 232.8, 234.7 [M+H]⁺.

b) 5-bromo-2-(methyloxy)-3-pyridinamine

To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol)in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772mmol). The reaction mixture was heated at reflux for 4 h. LC/MSindicated some starting material remained, so added 20 mol % tin (II)chloride dihydrate and continued to heat at reflux. After 2 h, thereaction was allowed to cool to ambient temperature and concentrated invacuo. The residue was treated with 2 N sodium hydroxide and the mixturestirred for 1 h. The mixture was then with methylene chloride (1 L),filtered through Celite, and washed with methylene chloride (500 mL).The layers were separated and the organics dried over magnesium sulfateand concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113mmol, 58.7% yield). The product was used crude in subsequent reactions.MS(ES)+ m/e 201.9, 203.9 [M+H]⁺.

c) N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

To a cooled (0° C.) solution of 5-bromo-2-(methyloxy)-3-pyridinamine(20.3 g, 100 mmol) in pyridine (200 mL) was added slowly2,4-difluorobenzenesulfonyl chloride (21.3 g, 100 mmol) over 15 min(reaction became heterogeneous). The ice bath was removed and thereaction was stirred at ambient temperature for 16 h, at which time thereaction was diluted with water (500 mL) and the solids filtered off andwashed with copious amounts of water. The precipitate was dried in avacuum oven at 50° C. to giveN-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (12g, 31.6 mmol, 31.7% yield) MS(ES)+ m/e 379.0, 380.9 [M+H]⁺.

*Other N-[5-bromo-2-(alkoxy)-3-pyridinyl]sulfonamides were or can beprepared using this procedure by varying the choice of sulfonyl chlorideand alkoxide.

Exemplary Capsule Composition

An oral dosage form for administering the present invention is producedby filing a standard two piece hard gelatin capsule with the ingredientsin the proportions shown in Table I, below.

TABLE I INGREDIENTS AMOUNTS compound of example 1 25 mg Lactose 55 mgTalc 16 mg Magnesium Stearate  4 mg

Exemplary Injectable Parenteral Composition

An injectable form for administering the present invention is producedby stirring 1.5% by weight of compound of example 1 in 10% by volumepropylene glycol in water.

Exemplary Tablet Composition

The sucrose, calcium sulfate dihydrate and an PI3K inhibitor as shown inTable II below, are mixed and granulated in the proportions shown with a10% gelatin solution. The wet granules are screened, dried, mixed withthe starch, talc and stearic acid; screened and compressed into atablet.

TABLE II INGREDIENTS AMOUNTS compound of example 1 20 mg calcium sulfatedehydrate 30 mg Sucrose  4 mg Starch  2 mg Talc  1 mg stearic acid 0.5mg 

While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

What is claimed is:
 1. A compound, which is2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide,or a pharmaceutically acceptable salt thereof.
 2. A compound, which isrepresented by the following structure


3. A pharmaceutically acceptable salt of a compound of claim
 1. 4. Apharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt of claim 1 and a pharmaceutically acceptable carrier.